Bromodomain inhibitors and uses thereof

ABSTRACT

The present invention relates to compounds useful as inhibitors of bromodomain-containing proteins. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.13/309,646, filed Dec. 2, 2011, which claims the benefit of U.S.Provisional application 61/419,119, filed on Dec. 2, 2010, and U.S.Provisional application 61/540,725 filed on Sep. 29, 2011. U.S.application Ser. No. 13/309,646 also claims the benefit of U.S.Provisional application 61/451,332, filed on Mar. 10, 2011; U.S.Provisional application 61/482,473, filed on May 4, 2011; and U.S.Provisional application 61/540,788, filed on Sep. 29, 2011. The entirecontents of the above-referenced applications are herein incorporated byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of oneor more bromodomain-containing proteins.

BACKGROUND OF THE INVENTION

Packaging the 3 billion nucleotides of the human genome into the nucleusof a cell requires tremendous compaction. To accomplish this feat, DNAin our chromosomes is wrapped around spools of proteins called histonesto form dense repeating protein/DNA polymers known as chromatin: thedefining template for gene regulation. Far from serving as merepackaging modules, chromatin templates form the basis of a newlyappreciated and fundamentally important set of gene control mechanismstermed epigenetic regulation. By conferring a wide range of specificchemical modifications to histones and DNA, epigenetic regulatorsmodulate the structure, function, and accessibility of our genome,thereby exerting a tremendous impact on gene expression. Hundreds ofepigenetic effectors have recently been identified, many of which arechromatin-binding proteins or chromatin-modifying enzymes.Significantly, an increasing number of these proteins have beenassociated with a variety of disorders such as neurodegenerativedisorders, metabolic diseases, inflammation, and cancer. Thus, highlyselective therapeutic agents directed against this emerging class ofgene regulatory proteins promise new approaches to the treatment ofhuman diseases.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   X is O or N;-   Y is O or N; wherein at least one of X or Y is O;-   R₁ is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, halo,    CN, OR_(A), NR_(A)R_(B), N(R_(A))S(O)_(q)R_(A)R_(B),    N(R_(A))C(O)R_(B), N(R_(A))C(O)NR_(A)R_(B), N(R_(A))C(O)OR_(A),    N(R_(A))C(S)NR_(A)R_(B), S(O)_(q)R_(A), C(O)R_(A), C(O)OR_(A),    OC(O)R_(A), or C(O)NR_(A)R_(B);    -   each R_(A) is independently optionally substituted alkyl,        optionally substituted alkenyl or optionally substituted        alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from        O, S, or N; optionally substituted aryl; optionally substituted        heteroaryl; optionally substituted heterocyclic; optionally        substituted carbocyclic; or hydrogen;    -   each R_(R) ^(C) is independently optionally substituted alkyl,        optionally substituted alkenyl or optionally substituted        alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from        O, S, or N; optionally substituted aryl; optionally substituted        heteroaryl; optionally substituted heterocyclic; optionally        substituted carbocyclic; or hydrogen; or    -   R_(A) and R_(B), together with the atoms to which each is        attached, can form a heterocycloalkyl or a heteroaryl; each of        which is optionally substituted;-   Ring A is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl;-   R^(C) is alkyl, alkenyl, alkynyl, cycloalkyl, aryl,    heterocycloalkyl, or heteroaryl, each optionally substituted with    1-5 independently selected R₄, and when L₁ is other than a covalent    bond, R^(C) is additionally selected from H;-   R₂ and R₃ are each independently H, halogen, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), or —(CH₂)_(p)R_(x);    or-   R₂ and R₃ together with the atoms to which each is attached, forms    an optionally substituted 3-7 membered saturated or unsaturated    spiro-fused ring having 0-3 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   each R_(x) is independently halogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);-   L¹ is a covalent bond or an optionally substituted bivalent C₁₋₆    hydrocarbon chain wherein one or two methylene units is optionally    replaced by —NR′—, —N(R′)C(O)—, —C(O)N(R′)—, —N(R′)SO₂—, —SO₂N(R′)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;-   each R is independently hydrogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, or optionally substituted heterocycloalkyl;-   each R′ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R groups on the same    nitrogen are taken together with their intervening atoms to form an    optionally substituted heteroaryl or heterocycloalkyl group;-   each R″ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R groups on the same    nitrogen are taken together with their intervening atoms to form an    optionally substituted heteroaryl or heterocycloalkyl group; or-   R′ and R″, together with the atoms to which each is attached, can    form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl;    each of which is optionally substituted;-   each R₄ is independently optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted heteroaryl, or    optionally substituted heterocycloalkyl, halogen, —OR, —SR,    —N(R′)(R″), —CN, —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″),    —C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R,    —SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   each R₅ is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN,    —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R,    —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   n is 0-5;-   each q is independently 0, 1, or 2; and-   p is 1-6.

In another aspect, the invention provides a method for inhibitingactivity of a bromodomain-containing protein, or a mutant thereof, in abiological sample comprising the step of contacting said biologicalsample with a compound of the invention (e.g., Formula I).

In another aspect, the invention provides a method for inhibitingactivity of a bromodomain-containing protein, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the invention (e.g., Formula I).

In another aspect, the invention provides a method for treating abromodomain-containing protein-mediated disorder in a patient in needthereof, comprising the step of administering to said patient a compoundof the invention (e.g., Formula I).

Provided compounds, and pharmaceutically acceptable compositionsthereof, are useful for treating a variety of diseases, disorders orconditions associated with abnormal cellular responses triggered byevents mediated by bromodomain-containing proteins. Such diseases,disorders, or conditions include those described herein.

Provided compounds are also useful for the study ofbromodomain-containing proteins in biological and pathologicalphenomena, the study of intracellular signal transduction pathwaysmediated by bromodomain-containing proteins, and the comparativeevaluation of new inhibitors of bromodomain-containing proteins.

DETAILED DESCRIPTION Compounds and Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito, 1999; Smith and March March's Advanced OrganicChemistry, 5^(th) Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987; the entirecontents of each of which are incorporated herein by reference.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

Where a particular enantiomer is preferred, it may, in some embodimentsbe provided substantially free of the corresponding enantiomer, and mayalso be referred to as “optically enriched.” “Optically-enriched,” asused herein, means that the compound is made up of a significantlygreater proportion of one enantiomer. In certain embodiments thecompound is made up of at least about 90% by weight of a preferredenantiomer. In other embodiments the compound is made up of at leastabout 95%, 98%, or 99% by weight of a preferred enantiomer. Preferredenantiomers may be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC) and the formation and crystallization of chiralsalts or prepared by asymmetric syntheses. See, for example, Jacques etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired products of the present invention.Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the compoundsdescribed herein are known in the art and include, for example, thosesuch as described in R. Larock, Comprehensive Organic Transformations,VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser andM. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, JohnWiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995), and subsequenteditions thereof.

The compounds of this invention may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

The number of carbon atoms in a hydrocarbyl substituent can be indicatedby the prefix “C_(X)-C_(y),” where x is the minimum and y is the maximumnumber of carbon atoms in the substituent.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, “haloalkyl” means an alkyl substituent wherein atleast one hydrogen radical is replaced with a halogen radical.

If a linking element in a depicted structure is “absent”, then the leftelement in the depicted structure is directly linked to the rightelement in the depicted structure. For example, if a chemical structureis depicted as X-L-Y wherein L is absent, then the chemical structure isX—Y.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

As used herein a “direct bond” or “covalent bond” refers to a single,double or triple bond. In certain embodiments, a “direct bond” or“covalent bond” refers to a single bond.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I).

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-6 carbon atoms. In someembodiments, aliphatic groups contain 1-4 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-3 carbon atoms. Aliphatic groupsinclude, but are not limited to, alkyl, alkenyl, alkynyl, carbocycle.Suitable aliphatic groups include, but are not limited to, linear orbranched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof suchas (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to asaturated or partially unsaturated cyclic aliphatic monocyclic orbicyclic ring systems, as described herein, having from 3 to 18 carbonring atoms, wherein the aliphatic ring system is optionally substitutedas defined above and described herein. Cycloaliphatic groups include,without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, and cyclooctadienyl. In some embodiments, the cycloalkylhas 3-6 carbons. The terms “cycloaliphatic”, “carbocycle”,“carbocyclyl”, “carbocyclo”, or “carbocyclic” also include aliphaticrings that are fused to one or more aromatic or nonaromatic rings, suchas decahydronaphthyl, tetrahydronaphthyl, decalin, orbicyclo[2.2.2]octane, where the radical or point of attachment is on analiphatic ring.

As used herein, the term “cycloalkylene” refers to a bivalent cycloalkylgroup. In certain embodiments, a cycloalkylene group is a1,1-cycloalkylene group (i.e., a spiro-fused ring). Exemplary1,1-cycloalkylene groups include

In other embodiments, a cycloalkylene group is a 1,2-cycloalkylene groupor a 1,3-cycloalkylene group. Exemplary 1,2-cycloalkylene groups include

The term “alkyl” as used herein, refers to a saturated, straight- orbranched-chain hydrocarbon radical typically containing from 1 to 20carbon atoms. For example, “C₁-C₈ alkyl” contains from one to eightcarbon atoms. Examples of alkyl radicals include, but are not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl, heptyl, octyl radicals and the like.

The term “alkenyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more double bonds and typicallyfrom 2 to 20 carbon atoms. For example, “C₂-C₈ alkenyl” contains fromtwo to eight carbon atoms. Alkenyl groups include, but are not limitedto, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl and the like.

The term “alkynyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more triple bonds and typicallyfrom 2 to 20 carbon atoms. For example, “C₂-C₈ alkynyl” contains fromtwo to eight carbon atoms. Representative alkynyl groups include, butare not limited to, for example, ethynyl, 1-propynyl, 1-butynyl,heptynyl, octynyl and the like.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to 15 ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains three to seven ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem which includes, but not limited to, phenyl, biphenyl, naphthyl,anthracyl and the like, which may bear one or more substituents. Theterm “aralkyl” or “arylalkyl” refers to an alkyl residue attached to anaryl ring. Examples of aralkyl include, but are not limited to, benzyl,phenethyl and the like. Also included within the scope of the term“aryl”, as it is used herein, is a group in which an aromatic ring isfused to one or more non-aromatic rings, such as indanyl, phthalimidyl,naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” includes but is not limited to nitrogen, oxygen, or sulfur,and includes any oxidized form of nitrogen or sulfur, and anyquaternized form of a basic nitrogen. A heteroaryl may be a single ring,or two or more fused rings. Heteroaryl groups include, withoutlimitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Theterms “heteroaryl” and “heteroar-”, as used herein, also include groupsin which a heteroaromatic ring is fused to one or more aryl,cycloaliphatic, or heterocyclyl rings, where the radical or point ofattachment is on the heteroaromatic ring. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- orbicyclic. The term “heteroaryl” may be used interchangeably with theterms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any ofwhich terms include rings that are optionally substituted. The term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl,wherein the alkyl and heteroaryl portions independently are optionallysubstituted. Examples include, but are not limited to, pyridinylmethyl,pyrimidinylethyl and the like.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl). Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl and the like.

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”,“heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and“heterocyclic radical”, are used interchangeably herein, and alsoinclude groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl,octahydroindolyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the heterocyclyl ring. A heterocyclyl group may bemono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl groupsubstituted by a heterocyclyl, wherein the alkyl and heterocyclylportions independently are optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms butis not aromatic. The term “partially unsaturated” is intended toencompass rings having multiple sites of unsaturation, but is notintended to include aryl or heteroaryl moieties, as herein defined.

The term “bivalent hydrocarbon” refers to a bivalent saturated orunsaturated hydrocarbon group. Such bivalent hydrocarbon groups includealkylene, alkenylene, and alkynylene groups.

The term “alkylene” refers to a divalent group derived from a straightor branched saturated hydrocarbyl chain typically containing from 1 to20 carbon atoms, more typically from 1 to 8 carbon atoms. Examples of an“alkylene” include a polymethylene group, i.e., —(CH₂)_(n)—, wherein nis a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3,from 1 to 2, or from 2 to 3; or —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—. A substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms arereplaced with a substituent. Suitable substituents include thosedescribed below for a substituted aliphatic group.

The term “alkenylene” refers to a divalent unsaturated hydrocarbyl groupwhich may be linear or branched and which has at least one carbon-carbondouble bond. An alkenylene group typically contains 2 to 20 carbonatoms, more typically from 2 to 8 carbon atoms. Non-limiting examples ofalkenylene groups include —C(H)═C(H)—, —C(H)═C(H)—CH₂—,—C(H)═C(H)—CH₂—CH₂—, —CH₂—C(H)═C(H)—CH₂—, —C(H)═C(H)—CH(CH₃)—, and—CH₂—C(H)═C(H)—CH(CH₂CH₃)—.

The term “alkynylene” refers to a divalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one carbon-carbontriple bond. Representative alkynylene groups include, by way ofexample, —C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —CH₂—C≡C—CH₂—, —C≡C—CH(CH₃)—,and —CH₂—C≡C—CH(CH₂CH₃)—.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at eachposition. Combinations of substituents envisioned under this inventionare preferably those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

The terms “optionally substituted”, “optionally substituted alkyl,”“optionally substituted alkenyl,” “optionally substituted alkynyl”,“optionally substituted carbocyclic,” “optionally substituted aryl”,“optionally substituted heteroaryl,” “optionally substitutedheterocyclic,” and any other optionally substituted group as usedherein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH-alkyl, —NH-alkenyl, —NH-alkynyl,—NH-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic,-dialkylamino, -diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH-alkynyl, —CONH— cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,

—OCO₂-alkyl, —OCO₂-alkenyl, —OCO₂-alkynyl, —OCO₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH-alkyl,—OCONH-alkenyl, —OCONH-alkynyl, —OCONH-cycloalkyl, —OCONH-aryl,—OCONH-heteroaryl, —OCONH-heterocycloalkyl,

—NHC(O)-alkyl, —NHC(O)-alkenyl, —NHC(O)— alkynyl, —NHC(O)-cycloalkyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl,—NHCO₂-alkyl, —NHCO₂-alkenyl, —NHCO₂— alkynyl, —NHCO₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH-alkyl, —NHC(O)NH-alkenyl, —NHC(O)NH-alkenyl,—NHC(O)NH-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH-alkyl,—NHC(S)NH-alkenyl, —NHC(S)NH— alkynyl, —NHC(S)NH-cycloalkyl,—NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl,—NHC(NH)NH₂, —NHC(NH)NH-alkyl, —NHC(NH)NH-alkenyl, —NHC(NH)NH-alkenyl,—NHC(NH)NH-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)-alkyl, —NHC(NH)-alkenyl,—NHC(NH)-alkenyl, —NHC(NH)-cycloalkyl, —NHC(NH)-aryl,—NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl,

—C(NH)NH-alkyl, —C(NH)NH-alkenyl, —C(NH)NH-alkynyl, —C(NH)NH-cycloalkyl,—C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl,

—S(O)-alkyl, —S(O)-alkenyl, —S(O)-alkynyl, —S(O)-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH-alkyl,—SO₂NH-alkenyl, —SO₂NH-alkynyl, —SO₂NH-cycloalkyl, —SO₂NH-aryl,—SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,

—NHSO₂-alkyl, —NHSO₂-alkenyl, —NHSO₂-alkynyl, —NHSO₂-cycloalkyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocycloalkyl, —CH₂NH₂,—CH₂SO₂CH₃,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy,-methoxyethoxy, —SH, —S-alkyl, —S-alkenyl, —S-alkynyl, —S-cycloalkyl,—S-aryl, —S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

In certain embodiments, suitable monovalent substituents on asubstitutable carbon atom of an “optionally substituted” group areindependently halogen; —(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘);—O—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄—CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘);—(CH₂)₀₋₄Ph, which may be substituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Phwhich may be substituted with R^(∘); —CH═CHPh, which may be substitutedwith R^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂;—(CH₂)₀₋₄N(R^(∘))C(O)R^(∘); —N(R^(∘))C(S)R^(∘);—(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄C(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘)S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(∘), taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, which may be substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(), -(haloR^()),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(), —(CH₂)₀₋₂CH(OR^())₂; —O(haloR^()), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(),—(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(),—(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃, —OSiR^() ₃, —C(O)SR^(), —(C₁₋₄straight or branched alkylene)C(O)OR^(), or —SSR^() wherein each R^()is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN, —C(O)OH,—C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein each R^() isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†)+ are independentlyhalogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “suitable amino protecting group,” includesthose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999.

Suitable amino-protecting groups include methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate,formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys),p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits the target bromodomain-containing protein (such as aBET protein, e.g., BRD2, BRD3, BRD4, and/or BRDT) with measurableaffinity. In certain embodiments, an inhibitor has an IC₅₀ and/orbinding constant of less about 50 μM, less than about 1 μM, less thanabout 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in activity of at least onebromodomain-containing protein between a sample comprising a providedcompound, or composition thereof, and at least one histonemethyltransferase, and an equivalent sample comprising at least onebromodomain-containing protein, in the absence of said compound, orcomposition thereof.

The term “subject” as used herein refers to a mammal A subject thereforerefers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, andthe like. Preferably the subject is a human. When the subject is ahuman, the subject may be either a patient or a healthy human.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts, or saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, or magnesium salts, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

Description of Exemplary Compounds

In one aspect, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   X is O or N;-   Y is O or N; wherein at least one of X or Y is O;-   R₁ is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, halo,    CN, OR_(A), NR_(A)R_(B), N(R_(A))S(O)_(q)R_(A)R_(B),    N(R_(A))C(O)R_(B), N(R_(A))C(O)NR_(A)R_(B), N(R_(A))C(O)OR_(A),    N(R_(A))C(S)NR_(A)R_(B), S(O)_(q)R_(A), C(O)R_(A), C(O)OR_(A),    OC(O)R_(A), or C(O)NR_(A)R_(B);    -   each R_(A) is independently optionally substituted alkyl,        optionally substituted alkenyl or optionally substituted        alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from        O, S, or N; optionally substituted aryl; optionally substituted        heteroaryl; optionally substituted heterocyclic; optionally        substituted carbocyclic; or hydrogen;    -   each R^(B) is independently optionally substituted alkyl,        optionally substituted alkenyl or optionally substituted        alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from        O, S, or N; optionally substituted aryl; optionally substituted        heteroaryl; optionally substituted heterocyclic; optionally        substituted carbocyclic; or hydrogen; or    -   R_(A) and R_(B), together with the atoms to which each is        attached, can form a heterocycloalkyl or a heteroaryl; each of        which is optionally substituted;-   Ring A is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl;-   R^(C) is alkyl, alkenyl, alkynyl, cycloalkyl, aryl,    heterocycloalkyl, or heteroaryl, each optionally substituted with    1-5 independently selected R⁴, and when L is other than a covalent    bond, R^(C) is additionally selected from H;-   R₂ and R₃ are each independently H, halogen, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), or —(CH₂)_(p)R_(x);    or-   R₂ and R₃ together with the atoms to which each is attached, forms    an optionally substituted 3-7 membered saturated or unsaturated    spiro-fused ring having 0-3 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   each R_(x) is independently halogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);-   L¹ is a covalent bond or an optionally substituted bivalent C₁₋₆    hydrocarbon chain wherein one or two methylene units is optionally    replaced by —NR′—, —N(R′)C(O)—, —C(O)N(R′)—, —N(R′)SO₂—, —SO₂N(R′)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;-   each R is independently hydrogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, or optionally substituted heterocycloalkyl;-   each R′ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R groups on the same    nitrogen are taken together with their intervening atoms to form an    optionally substituted heteroaryl or heterocycloalkyl group;-   each R″ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R groups on the same    nitrogen are taken together with their intervening atoms to form an    optionally substituted heteroaryl or heterocycloalkyl group; or-   R′ and R″, together with the atoms to which each is attached, can    form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl;    each of which is optionally substituted;-   each R₄ is independently optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted heteroaryl, or    optionally substituted heterocycloalkyl, halogen, —OR, —SR,    —N(R′)(R″), —CN, —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″),    —C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R,    —SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   each R₅ is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN,    —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R,    —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   n is 0-5;-   each q is independently 0, 1, or 2; and-   p is 1-6.

In one embodiment, the invention provides a compound of formula II orformula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   R₁ is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, halo,    CN, OR_(A), NR_(A)R_(B), N(R_(A))S(O)_(q)R_(A)R_(B),    N(R_(A))C(O)R_(B), N(R_(A))C(O)NR_(A)R_(B), N(R_(A))C(O)OR_(A),    N(R_(A))C(S)NR_(A)R_(B), S(O)_(q)R_(A), C(O)R_(A), C(O)OR_(A),    OC(O)R_(A), or C(O)NR_(A)R_(B);    -   each R_(A) is independently optionally substituted alkyl,        optionally substituted alkenyl or optionally substituted        alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from        O, S, or N; optionally substituted aryl; optionally substituted        heteroaryl; optionally substituted heterocyclic; optionally        substituted carbocyclic; or hydrogen;    -   each R_(B) is independently optionally substituted alkyl,        optionally substituted alkenyl or optionally substituted        alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from        O, S, or N; optionally substituted aryl; optionally substituted        heteroaryl; optionally substituted heterocyclic; optionally        substituted carbocyclic; or hydrogen; or    -   R_(A) and R_(B), together with the atoms to which each is        attached, can form a heterocycloalkyl or a heteroaryl; each of        which is optionally substituted;-   Ring A is a 5-6 membered fused aryl ring; a 5-6 membered fused    heteroaryl ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, or sulfur; an 8-12 membered bicyclic aryl ring; or    an 8-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   R^(C) is alkyl, alkenyl, alkynyl, a 3-7 membered saturated,    partially unsaturated or completely unsaturated carbocyclic ring; a    3-7 membered aryl ring; an 8-12 membered bicyclic saturated,    partially unsaturated, or completely unsaturated carbocyclic ring;    an 8-12 membered bicyclic aryl ring; a 3-7 membered saturated,    partially unsaturated, or completely unsaturated heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    and sulfur; a 3-7 membered monocyclic heteroaryl ring having 1-3    heteroatoms independently selected from nitrogen, oxygen, and    sulfur; a 7-10 membered bicyclic saturated, partially unsaturated,    or completely unsaturated heterocyclic ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; or a 7-10    membered bicyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, each    optionally substituted with 1-5 independently selected R⁴, and when    L is other than a covalent bond, R^(C) is additionally selected from    H;-   R₂ and R₃ are each independently H, halogen, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), or —(CH₂)_(p)R_(x);    or-   R₂ and R₃ together with the atoms to which each is attached, forms    an optionally substituted 3-7 membered saturated or partially    unsaturated spiro-fused ring having 0-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;-   each R_(x) is independently halogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);-   L¹ is a covalent bond or an optionally substituted bivalent C₁₋₆    hydrocarbon chain wherein one or two methylene units is optionally    replaced by —NR′—, —N(R′)C(O)—, —C(O)N(R′)—, —N(R′)SO₂—, —SO₂N(R′)—,    —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;-   each R is independently hydrogen, C₁₋₆ aliphatic, a 5-6 membered    aryl ring, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated carbocyclic ring, a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated    carbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or a 7-12 membered    bicyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    optionally substituted;-   each R′ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted;-   each R″ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted; or-   R′ and R″, together with the atoms to which each is attached, can    form a 3-7 membered monocyclic saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated fused heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 3-7    membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic    heteroaryl; each of which is optionally substituted;-   each R₄ is independently optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted heteroaryl, or    optionally substituted heterocycloalkyl, halogen, —OR, —SR,    —N(R′)(R″), —CN, —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″),    —C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R,    —SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   each R₅ is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN,    —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R,    —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   n is 0-5;-   each q is independently 0, 1, or 2; and-   p is 1-6.

In certain embodiments, Ring A is benzo or a 5-6 membered fusedheteroaryl ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In other embodiments, R^(C) is a 3-7 membered aryl ring; 3-7 memberedsaturated or partially unsaturated carbocyclic ring or a 4-7 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R^(C) is optionally substituted with 1-5 independently selectedR⁴.

In various embodiments, R₂ is H, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R,—CO₂R, —C(O)N(R′)(R″), —C(O)SR, or —(CH₂)_(p)R_(x).

In still other embodiments, R₃ is H, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R,—CO₂R, —C(O)N(R′)(R″), —C(O)SR, or —(CH₂)_(p)R_(x).

In certain embodiments, R₂ and R₃, together with the atoms to which eachis attached, forms an optionally substituted 3-7 membered saturated orpartially unsaturated spiro-fused ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In other embodiments, when X is N and Y is O, R₁ is H, alkyl, alkenyl,alkynyl, aralkyl, aryl, heteroaryl, halo, CN, OR_(A), NR_(A)R_(B),N(R_(A))S(O)_(q)R_(A)R_(B), N(R_(A))C(O)R_(B), N(R_(A))C(O)NR_(A)R_(B),N(R_(A))C(O)OR_(A), N(R_(A))C(S)NR_(A)R_(B), S(O)_(q)R_(A), C(O)R_(A),C(O)OR_(A), OC(O)R_(A), or C(O)NR_(A)R_(B); with the proviso that R₁ isnot —OH.

In other embodiments, when X is N and Y is O, the compound is not6-phenyl-4H-benzo[c]isoxazolo[4,5-e]azepin-1-ol.

In other embodiments, when X is N and Y is O, L₁ is a covalent bond andR^(C) is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, orheteroaryl, each optionally substituted with 1-5 independently selectedR⁴, or aryl substituted with 1-5 independently selected R⁴.

In other embodiments, when X is N and Y is O, R^(C) is aryl substitutedwith 1-5 independently selected R⁴.

In another embodiment, L₁ is a covalent bond and the invention providesa compound of formula II-A:

or a pharmaceutically acceptable salt thereof, wherein:

-   R₁ is H, alkyl, aralkyl, aryl, heteroaryl, halo, OR_(A),    NR_(A)R_(B), S(O)_(q)R_(A), C(O)R_(A), C(O)OR_(A),

OC(O)R_(A), or C(O)NR_(A)R_(B);

-   -   each R_(A) is independently optionally substituted alkyl,        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        optionally substituted aryl; optionally substituted heteroaryl;        optionally substituted heterocyclic; optionally substituted        carbocyclic; or hydrogen;    -   each R_(B) is independently optionally substituted alkyl,        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        optionally substituted aryl; optionally substituted heteroaryl;        optionally substituted heterocyclic; optionally substituted        carbocyclic; or hydrogen;

-   Ring A is benzo or a 5-6 membered fused heteroaryl ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    which is optionally substituted;

-   R^(C) is a 3-7 membered saturated, partially unsaturated or    completely unsaturated carbocyclic ring; a 3-7 membered aryl ring;    or a 3-7 membered saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, wherein R^(C) is    optionally substituted with 1-5 independently selected R⁴;

-   R₂ and R₃ are each independently H, halogen, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, C(O)N(R′)(R″), —C(O)SR, or    —(CH₂)_(p)R_(x); or

-   R₂ and R₃ together with the atoms to which each is attached, forms    an optionally substituted 3-7 membered saturated or partially    unsaturated spiro-fused ring having 0-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;

-   each R_(x) is independently halogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);

-   each R is independently hydrogen, C₁₋₆ aliphatic, a 5-6 membered    aryl ring, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated carbocyclic ring, a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated    carbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or a 7-12 membered    bicyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    optionally substituted;

-   each R′ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted;

-   each R″ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted; or

-   R′ and R″, together with the atoms to which each is attached, can    form a 3-7 membered monocyclic saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated fused heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 3-7    membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic    heteroaryl; each of which is optionally substituted;

-   each R₄ is independently optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted heteroaryl, or    optionally substituted heterocycloalkyl, halogen, —OR, —SR,    —N(R′)(R″), —CN, —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″),    —C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R,    —SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);

-   each R₅ is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN, or    —NO₂;

-   n is 0-5;

-   q is 0, 1, or 2; and

-   p is 1-6.

In other embodiments, L₁ is a covalent bond and the invention provides acompound of formula III-A:

or a pharmaceutically acceptable salt thereof, wherein:

-   R₁ is H, alkyl, aralkyl, aryl, heteroaryl, halo, OR_(A),    NR_(A)R_(B), S(O)_(q)R_(A), C(O)R_(A), C(O)OR_(A), OC(O)R_(A), or    C(O)NR_(A)R_(B);    -   each R_(A) is independently optionally substituted alkyl,        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        optionally substituted aryl; optionally substituted heteroaryl;        optionally substituted heterocyclic; optionally substituted        carbocyclic; or hydrogen;    -   each R_(B) is independently optionally substituted alkyl,        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        optionally substituted aryl; optionally substituted heteroaryl;        optionally substituted heterocyclic; optionally substituted        carbocyclic; or hydrogen; or    -   R_(A) and R_(B), together with the atoms to which each is        attached, can form a cycloalkyl, a heterocycloalkyl, an aryl, or        a heteroaryl; each of which is optionally substituted;-   Ring A is benzo or a 5-6 membered fused heteroaryl ring having 1-2    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    which is optionally substituted;-   R^(C) is a 3-7 membered saturated, partially unsaturated or    completely unsaturated carbocyclic ring; a 3-7 membered aryl ring;    or a 3-7 membered saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, wherein R^(C) is    optionally substituted with 1-5 independently selected R⁴;-   R₂ and R₃ are each independently H, halogen, optionally substituted    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, or    —(CH₂)_(p)R_(x); or-   R₂ and R₃ together with the atoms to which each is attached, forms    an optionally substituted 3-7 membered saturated or partially    unsaturated spiro-fused ring having 0-3 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;-   each R_(x) is independently halogen, optionally substituted alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN,    —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR,    —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);-   each R is independently hydrogen, C₁₋₆ aliphatic, a 5-6 membered    aryl ring, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated carbocyclic ring, a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated    carbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or a 7-12 membered    bicyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    optionally substituted;-   each R′ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted;-   each R″ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted; or-   R′ and R″, together with the atoms to which each is attached, can    form a 3-7 membered monocyclic saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated fused heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 3-7    membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic    heteroaryl; each of which is optionally substituted;-   each R₄ is independently optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted heteroaryl, or    optionally substituted heterocycloalkyl, halogen, —OR, —SR,    —N(R′)(R″), —CN, —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″),    —C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R,    —SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R′)(R″);-   each R₅ is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN, or    —NO₂;-   n is 0-5;-   q is 0, 1, or 2; and-   p is 1-6.

In certain embodiments, Ring A is a 6-membered fused heteroaryl ringhaving 1-2 nitrogen atoms. In a further embodiment, Ring A is pyrido,pyrimidino, pyrazino, or pyridazino.

In various embodiments, Ring A is a 5-membered fused heteroaryl ringhaving 1 heteroatom selected from nitrogen, oxygen, or sulfur. In afurther embodiment, Ring A is thieno.

In other embodiments, Ring A is a 5-membered fused heteroaryl ringhaving 2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In a further embodiment, Ring A is isothiazolo.

In another embodiment, Ring A is benzo.

In certain embodiments, R^(C) is phenyl or a 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In a furtherembodiment, R^(C) is piperidinyl, morpholinyl, or piperazinyl. In eachof the above embodiments, R^(C) is optionally substituted with 1-5independently selected R⁴.

In other embodiments, R₁ is halo, alkyl, aralkyl, aryl, or heteroaryl.In a further embodiment, R₁ is methyl, ethyl, propyl, i-propyl, butyl,s-butyl, t-butyl, pentyl, hexyl, or heptyl.

In another embodiment, R₂ is H, methyl, ethyl, propyl, i-propyl, butyl,s-butyl, pentyl, hexyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R,—CO₂R, —C(O)N(R′)(R″), —C(O)SR, or —(CH₂)_(p)R_(x). In a furtherembodiment, R₂ is H or —(CH₂)_(p)R_(x).

In certain embodiments, R_(x) is —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R,—C(O)N(R′)(R″), —C(S)N(R′)(R″), —S(O)R, —SO₂R, —SO₂N(R′)(R″),—N(R′)C(O)R, —N(R′)SO₂R, —OC(O)R, —OC(O)N(R′)(R″), methyl, ethyl,propyl, i-propyl, butyl, s-butyl, pentyl or hexyl.

In other embodiments, R₃ is H, methyl, ethyl, propyl, i-propyl, butyl,s-butyl, pentyl, hexyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R,—CO₂R, —C(O)N(R′)(R″), —C(O)SR, or —(CH₂)_(p)R_(x). In a furtherembodiment, R₂ is H or —(CH₂)_(p)R_(x).

In certain embodiments, R_(x) is —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R,—C(O)N(R′)(R″), —C(S)N(R′)(R″), —S(O)R, —SO₂R, —SO₂N(R′)(R″),—N(R′)C(O)R, —N(R′)SO₂R, —OC(O)R, —OC(O)N(R′)(R″), methyl, ethyl,propyl, i-propyl, butyl, s-butyl, pentyl or hexyl.

In certain embodiments, R₂ and R₃ together with the atoms to which eachis attached, forms an optionally substituted 3-7 membered saturated orpartially unsaturated spiro-fused ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In a furtherembodiment, R₂ and R₃ together with the atoms to which each is attached,forms an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, azetidine, oxetane, tetrahydrofuran, or pyrrolidine.

In a further embodiment, R₂ and R₃ are optionally substituted byhalogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heteroaryl,heterocycloalkyl, each of which is further optionally substituted; or

R₂ and R₃ are optionally substituted by —OR, —SR, —CN, —N(R′)(R″),—C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R,—C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R, —SO₂N(R′)(R″),—N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R,—N(R′)SO₂N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″),—C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″), or—(CH₂)_(p)R_(x).

In various embodiments,

-   R_(x) is halogen, optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted heteroaryl,    optionally substituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″),    —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R,    —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO₂R,    —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),    —N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″),    —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR,    —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);-   each R is independently hydrogen, C₁₋₆ aliphatic, a 5-6 membered    aryl ring, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated carbocyclic ring, a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated    carbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, a 3-7 membered saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or a 7-12 membered    bicyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; each of which is    optionally substituted;-   each R′ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted;-   each R″ is independently —R, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂,    —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on the same nitrogen    are taken together with their intervening atoms to form a 3-7    membered monocyclic saturated, partially unsaturated, or completely    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic    saturated, partially unsaturated, or completely unsaturated fused    heterocyclic ring having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl    ring; or a 7-12 membered bicyclic heteroaryl; each of which is    optionally substituted; or-   R′ and R″, together with the atoms to which each is attached, can    form a 3-7 membered monocyclic saturated, partially unsaturated, or    completely unsaturated heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 7-12    membered bicyclic saturated, partially unsaturated, or completely    unsaturated fused heterocyclic ring having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur; a 3-7    membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic    heteroaryl; each of which is optionally substituted.

In each of the embodiments of R^(C) set forth below, R^(C) is optionallysubstituted with 1-5 independently selected R⁴.

In some embodiments, R^(C) is phenyl.

In some embodiments, R^(C) is a 3-7 membered saturated or partiallyunsaturated carbocyclic ring. In certain embodiments, R^(C) iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Incertain embodiments, R^(C) is cyclopentenyl, cyclohexenyl, orcycloheptenyl.

In some embodiments, R^(C) is a 4-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In certain embodiments,R^(C) is a 5-6 membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In certain embodiments, R^(C) is tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, oxazolidinyl,piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl,or morpholinyl.

In some embodiments, R^(C) is a 5-6 membered monocyclic heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In certain embodiments, R^(C) is 6-membered heteroaryl ring having 1-3nitrogen atoms. In other embodiments, R^(C) is a 6-membered heteroarylring having 1 nitrogen atom. In certain other embodiments, R^(C) is a6-membered heteroaryl ring having 2 nitrogen atoms. In yet otherembodiments, R^(C) is a 6-membered heteroaryl ring having 3 nitrogenatoms.

In other embodiments, R^(C) is a 5-membered heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R^(C) is a 5-membered heteroaryl ring having 1heteroatom independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R^(C) is a 5-membered heteroaryl ring having 2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inother embodiments, R^(C) is a 5-membered heteroaryl ring having 2heteroatoms independently selected from nitrogen and oxygen. In someembodiments, R^(C) is a 5-membered heteroaryl ring having 2 heteroatomsindependently selected from nitrogen and sulfur. In other embodiments,R^(C) is a 5-membered heteroaryl ring having 1-3 nitrogen atoms. Incertain embodiments, R^(C) is thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, or pyrazinyl.

In some embodiments, R^(C) is a 7-10 membered bicyclic saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or an 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In certain embodiments,R^(C) is a 5,5-fused-, 5,6-fused, or 6,6-fused saturated, partiallyunsaturated, or aromatic bicyclic ring. In some embodiments, R^(C) is a5,5-fused, 5,6-fused, or 6,6-fused aromatic bicyclic ring. In otherembodiments, R^(C) is a naphthalenyl, indanyl or indenyl group.

In some embodiments, R^(C) is a 7-10 membered bicyclic saturated orpartially unsaturated heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, R^(C) is a 7-8 membered bicyclic saturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In certain embodiments, R^(C) is a 7-8 memberedbicyclic partially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, R^(C) is a 9-10 membered bicyclic saturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In certain embodiments, R^(C) is a 9-10 memberedbicyclic partially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, R^(C) is tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, or quinuclidinyl. In certain embodiments, R^(C) isindolinyl, 3H-indolyl, chromanyl, phenanthridinyl,2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

In some embodiments, R^(C) is a 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In some embodiments, R^(C) is a 5,5-fused, 5,6-fused, or 6,6-fusedsaturated, partially unsaturated, or aromatic bicyclic ring having 1-4heteroatoms, independently selected from nitrogen, oxygen, or sulfur. Inother embodiments, R^(C) is a 5,5-fused, 5,6-fused, or 6,6-fusedheteroaryl ring having 1-4 heteroatoms, independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, R^(C) is a5,5-fused, 5,6-fused, or 6,6-fused heteroaryl ring having 1-4 nitrogenatoms. In other embodiments, R^(C) is a 5,6-fused heteroaryl ring having1-4 nitrogen atoms. In certain embodiments, R^(C) is pyrrolizinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl,indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl,naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl. Incertain embodiments, R^(C) is a indolizinyl, purinyl, naphthyridinyl, orpteridinyl.

In certain embodiments, L₁ is a covalent bond and the invention providesa compound of Formula IV:

wherein:

R^(C) is selected from phenyl, cycloalkyl, heteroaryl, saturatedheterocyclyl and alkyl, wherein any ring portion of R^(C) is optionallysubstituted with 1 to 2 substituents independently selected from halo,alkyl, oxo, amino, alkylcarbonylamino, carbamyl, and —CN; and

R′ is selected from hydrogen, alkyl and fluoroalkyl.

In certain embodiments of Formula IV, R^(C) is selected from1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-3-yl, pyrimidin-5-yl,pyridazin-4-yl, 2-aminopyridin-5-yl, pyridin-3-yl, pyridin-4-yl, phenyl,4-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 2-methyl-4-chlorophenyl,4-cyanophenyl, 4-carbamylphenyl, 3-carbamylphenyl, 4-acetylaminophenyl,1-methylpyridin-2(1H)-one-4-yl, 1-methylpyridin-2(1H)-one-5-yl,4-methylpiperazin-1-yl, morpholin-4-yl, 1-methyl-1,4-diazepan-4-yl,propyl, cyclopropyl, cyclohexyl, and tetrahydro-2H-pyran-4-yl.

In certain embodiments of Formula IV, R′ is selected from hydrogen,ethyl, and 2-fluoroethyl.

In certain embodiments, the invention provides a compound of Formula V:

wherein:R_(5a) is selected from hydrogen, halo, and alkoxy;R_(5b) is selected from hydrogen, halo, and alkyl;R^(C) is selected from phenyl, heteroaryl, and saturated heterocyclyl,wherein R^(C) is optionally substituted with 1 to 2 substituentsindependently selected from halo, —CN, alkyl, alkoxy, haloalkoxy,haloalkyl, and carbamyl; andR′ is selected from hydrogen, alkyl, and alkoxyalkyl.

In some embodiments of Formula V, R_(5a) is selected from hydrogen,chloro, and methoxy.

In some embodiments of Formula V, R_(5b) is selected from hydrogen,chloro, and methyl.

In some embodiments of Formula V, R_(5a) and R_(5b) are simultaneouslyhydrogen

In some embodiments of Formula V, R^(C) is selected from 4-chlorophenyl,4-cyanophenyl, 4-fluorophenyl, pyridin-4-yl, 4-trifluoromethylphenyl,5-chloropyridin-2-yl, 4-carbamylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-trifluoromethoxyphenyl, 2-methyl-4-chlorophenyl, andmorpholin-4-yl.

In some embodiments of Formula V, R′ is selected from hydrogen, ethyl,and 2-methoxyethyl.

Exemplary compounds of the invention are set forth in Tables 1-4 below.

TABLE 1 Exemplary Compounds Compounds of the invention include thefollowing:

TABLE 2 Exemplary Compounds of Formula IV: (IV)

Cmpd No. R^(C) R′ 100

H 101

H 102

H 103

H 104

H 105

H 106

H 107

H 108

H 109

H 110

H 111

H 112

H 113

Et 114

115

H 116

H 117

H 118

H 119

H 120

H 121

H 122

H 123

H 124

H 125

H 126

H 165

Et 168

H

TABLE 3 Exemplary Compounds of Formula V: (V)

Cmpd No. R_(5a) R_(5b) R^(C) R′ 128 H Me

H 129 H Me

H 130 H Me

H 131 H Me

H 132 H Me

H 133 H Me

H 134 H Me

H 135 H Me

H 136 H Me

H 137 H Cl

H 138 H Cl

H 139 H Cl

H 140 H Cl

H 141 Cl H

H 142 Cl H

H 143 Cl H

Et 144 H H

H 145 H H

146 H H

H 147 H H

H 148 H H

H 149 H H

Et 150 H H

151 H H

H 152 H H

H 159 H H

Et 160 OMe H

Et

TABLE 4 Additional Exemplary Compounds of the Invention. Cmpd NoStructure 127

153

154

155

156

157

158

161

162

163

164

166

167

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

In certain embodiments, the present invention provides a method ofinhibiting a bromodomain-containing protein (such as a BET protein,e.g., BRD2, BRD3, BRD4, and/or BRDT) comprising contacting saidbromodomain-containing protein with any compound depicted in the tablesherein, or a pharmaceutically acceptable salt or composition thereof.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the present invention provides a methodof inhibiting a bromodomain-containing protein (such as a BET protein,e.g., BRD2, BRD3, BRD4, and/or BRDT) using a composition comprising acompound of the invention or a pharmaceutically acceptable derivativethereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The amount of a compound of the invention in a provided composition issuch that is effective to measurably inhibit one or morebromodomain-containing proteins (such as a BET protein, e.g., BRD2,BRD3, BRD4, and/or BRDT), or a mutant thereof, in a biological sample orin a patient. In certain embodiments, the amount of compound in aprovided composition is such that is effective to measurably inhibit oneor more bromodomain-containing proteins (such as a BET protein, e.g.,BRD2, BRD3, BRD4, and/or BRDT), or a mutant thereof, in a biologicalsample or in a patient. In certain embodiments, a provided compositionis formulated for administration to a patient in need of suchcomposition. In some embodiments, a provided composition is formulatedfor oral administration to a patient.

The term “patient,” as used herein, means an animal, such as a mammal,such as a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this disclosure include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitory active metabolite or residue thereof.

As used herein, the term “inhibitory active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof one or more bromodomain-containing proteins (such as a BET protein,e.g., BRD2, BRD3, BRD4, and/or BRDT), or a mutant thereof.

Compositions described herein may be administered orally, parenterally,by inhalation spray, topically, rectally, nasally, buccally, vaginallyor via an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a provided compound, it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

Provided compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Pharmaceutically acceptable compositions provided herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promotors to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Pharmaceutically acceptable compositions provided herein may beformulated for oral administration. Such formulations may beadministered with or without food. In some embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered withoutfood. In other embodiments, pharmaceutically acceptable compositions ofthis disclosure are administered with food.

The amount of provided compounds that may be combined with carriermaterials to produce a composition in a single dosage form will varydepending upon the patient to be treated and the particular mode ofadministration. Provided compositions may be formulate such that adosage of between 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, the judgment of thetreating physician, and the severity of the particular disease beingtreated. The amount of a provided compound in the composition will alsodepend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of activity of one or more proteins involved in epigeneticregulation. Thus, in some embodiments, the present invention provides amethod of inhibiting one or more proteins involved in epigeneticregulation, such as proteins containing acetyl-lysine recognitionmotifs, also known as bromodomains (e.g., BET proteins, such as BRD2,BRD3, BRD4, and/or BRDT), by administering a provided compound orcomposition.

Epigenetics is the study of heritable changes in gene expression causedby mechanisms other than changes in the underlying DNA sequence.Molecular mechanisms that play a role in epigenetic regulation includeDNA methylation and chromatin/histone modifications. Chromatinrecognition, in particular, is critical in many epigenetic phenomena.

Chromatin, the organized assemblage of nuclear DNA and histone proteins,is the basis for a multitude of vital nuclear processes includingregulation of transcription, replication, DNA-damage repair andprogression through the cell cycle. A number of factors, such aschromatin-modifying enzymes, have been identified that play an importantrole in maintaining the dynamic equilibrium of chromatin (Margueron, etal. (2005) Curr. Opin. Genet. Dev. 15:163-176).

Histones are the chief protein components of chromatin. They act asspools around which DNA winds, and they play a role in gene regulation.There are a total of six classes of histones (H1, H2A, H2B, H3, H4, andH5) organized into two super classes: core histones (H2A, H2B, H3, andH4) and linker histones (H1 and H5). The basic unit of chromatin is thenucleosome, which consists of about 147 base pairs of DNA wrapped aroundthe histone octamer, consisting of two copies each of the core histonesH2A, H2B, H3, and H4 (Luger, et al. (1997) Nature 389:251-260).

Histones, particularly residues of the amino termini of histones H3 andH4 and the amino and carboxyl termini of histones H2A, H2B and H1, aresusceptible to a variety of post-translational modifications includingacetylation, methylation, phosphorylation, ribosylation sumoylation,ubiquitination, citrullination, deimination, and biotinylation. The coreof histones H2A and H3 can also be modified. Histone modifications areintegral to diverse biological processes such as gene regulation, DNArepair, and chromosome condensation.

One type of histone modification, lysine acetylation, is recognized bybromodomain-containing proteins. Bromodomain-containing proteins arecomponents of transcription factor complexes and determinants ofepigenetic memory (Dey, et al. (2009) Mol. Biol. Cell 20:4899-4909).There are 46 human proteins containing a total of 57 bromodomainsdiscovered to date. One family of bromodomain-containing proteins, BETproteins (BRD2, BRD3, BRD4, and BRDT) have been used to establishproof-of-concept for targeting protein-protein interactions ofepigenetic “readers,” as opposed to chromatin-modifying enzymes, orso-called epigenetic “writers” and “erasers” (Filippakopoulos, et al.“Selective Inhibition of BET Bromodomains,” Nature (published onlineSep. 24, 2010); Nicodeme, et al. “Suppression of Inflammation by aSynthetic Histone Mimic,” Nature (published online Nov. 10, 2010)).

Examples of proteins inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include bromodomain-containing proteins, such as BET proteins,such as BRD2, BRD3, BRD4, and/or BRDT, or an isoform or mutant thereof.

The activity of a provided compound, or composition thereof, as aninhibitor of a bromodomain-containing protein, such as a BET protein,such as BRD2, BRD3, BRD4, and/or BRDT, or an isoform or mutant thereof,may be assayed in vitro, in vivo, or in a cell line. In vitro assaysinclude assays that determine inhibition of bromodomain-containingproteins, such as BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT,or a mutant thereof. Alternatively, inhibitor binding may be determinedby running a competition experiment where a provided compound isincubated with a bromodomain-containing protein, such as a BET protein,such as BRD2, BRD3, BRD4, and/or BRDT bound to known ligands, labeled orunlabeled. Detailed conditions for assaying a provided compound as aninhibitor of a bromodomain-containing protein, such as a BET protein,such as BRD2, BRD3, BRD4, and/or BRDT or a mutant thereof, are set forthin the Examples below.

The invention provides for a method of treating a subject with aMYC-dependent cancer, comprising: identifying a subject in need oftreatment; administering to the subject a BET inhibitor; determining atleast one of MYC mRNA expression, MYC protein expression and tumor mass,and wherein following administration, there is a decrease in at leastone of myc mRNA expression, MYC protein expression and tumor mass,thereby treating the disease.

In one embodiment, the identification step comprises determining whetherthe subject has at least one of a MYC translocation, a geneticrearrangement of MYC, MYC amplification, MYC over-expression and atleast one cellular function that facilitates cellular and/or tumorgrowth and is altered upon reduction of myc mRNA or protein expression.

The invention also provides for a method of treating a subject with aMYC-dependent cancer, comprising: determining at least one of MYC mRNAexpression, MYC protein expression and tumor mass; administering to thesubject a BET inhibitor; and comparing at least one of MYC mRNAexpression, MYC protein expression and tumor mass in the subject beforeand after administration of the BET inhibitor.

The invention also provides a method of treating a subject with aMYC-dependent cancer, comprising: administering to the subject a BETinhibitor that is identified as capable of decreasing at least one ofmyc mRNA expression, MYC protein expression and tumor mass; anddetermining at least one of myc mRNA expression, MYC protein expressionand tumor mass; wherein following the administration, there is adecrease in at least one of myc mRNA expression, MYC protein expressionand tumor mass, thereby treating the disease.

The invention also provides for a method of treating a subject with adisease, comprising: administering a BET inhibitor that is identified ascapable of decreasing at least one of myc mRNA expression, MYC proteinexpression and tumor mass, wherein following the administration, thereis a decrease in at least one of myc mRNA expression, MYC proteinexpression and tumor mass, thereby treating the disease.

Acetylated histone recognition and bromodomain-containing proteins (suchas BET proteins) have been implicated in proliferative disease. BRD4knockout mice die shortly after implantation and are compromised intheir ability to maintain an inner cell mass, and heterozygotes displaypre- and postnatal growth defects associated with reduced proliferationrates. BRD4 regulates genes expressed during M/G1, includinggrowth-associated genes, and remains bound to chromatin throughout thecell cycle (Dey, et al. (2009) Mol. Biol. Cell 20:4899-4909). BRD4 alsophysically associates with Mediator and P-TEFb (CDK9/cyclin T1) tofacilitate transcriptional elongation (Yang, et al. (2005) Oncogene24:1653-1662; Yang, et al. (2005) Mol. Cell. 19:535-545). CDK9 is avalidated target in chronic lymphocytic leukemia (CLL), and is linked toc-Myc-dependent transcription (Phelps, et al. Blood 113:2637-2645; Rahl,et al. (2010) Cell 141:432-445).

BRD4 is translocated to the NUT protein in patients with lethal midlinecarcinoma, an aggressive form of human squamous carcinoma (French, etal. (2001) Am. J. Pathol. 159:1987-1992; French, et al. (2003) CancerRes. 63:304-307). In vitro analysis with RNAi supports a causal role forBRD4 in this recurrent t(15; 19) chromosomal translocation.Pharmacologic inhibition of the BRD4 bromodomains results in growtharrest/differentiation of BRD4-NUT cell lines in vitro and in vivo(Filippakopoulos, et al. “Selective Inhibition of BET Bromodomains,”Nature (published online Sep. 24, 2010)).

Bromodomain-containing proteins (such as BET proteins) have also beenimplicated in inflammatory diseases. BET proteins (e.g., BRD2, BRD3,BRD4, and BRDT) regulate assembly of histone acetylation-dependentchromatin complexes that control inflammatory gene expression(Hargreaves, et al. (2009) Cell 138:129-145; LeRoy, et al. (2008) Mol.Cell. 30:51-60; Jang, et al. (2005) Mol. Cell. 19:523-534; Yang, et al.(2005) Mol. Cell. 19:535-545). Key inflammatory genes (secondaryresponse genes) are down-regulated upon bromodomain inhibition of theBET subfamily, and non-responsive genes (primary response genes) arepoised for transcription. BET bromodomain inhibition protects againstLPS-induced endotoxic shock and bacteria-induced sepsis in vivo(Nicodeme, et al. “Suppression of Inflammation by a Synthetic HistoneMimic,” Nature (published online Nov. 10, 2010)).

Bromodomain-containing proteins (such as BET proteins) also play a rolein viral disease. For example, BRD4 is implicated in human papillomavirus (HPV). In the primary phase of HPV infection of basal epithelia,the viral genome is maintained in an extra-chromosomal episome. In somestrains of HPV, BRD4 binding to the HPV E2 protein functions to tetherthe viral genome to chromosomes. E2 is critical for both the repressionof E6/E7 and to activation of HPV viral genes. Disruption of BRD4 or theBRD4-E2 interaction blocks E2-dependent gene activation. BRD4 alsofunctions to tether other classes of viral genomes to host chromatin(e.g., Herpesvirus, Epstein-Barr virus).

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

In certain embodiments, a provided compound inhibits one or more ofBRD2, BRD3, BRD4, BRDT, and/or another member of thebromodomain-containing proteins, or a mutant thereof. In someembodiments, a provided compound inhibits two or more of BRD2, BRD3,BRD4, BRDT, and/or another member of the bromodomain-containingproteins, or a mutant thereof. Provided compounds are inhibitors of oneof more of the bromodomain-containing proteins, such as BRD2, BRD3,BRD4, and/or BRDT and are therefore useful for treating one or moredisorders associated with activity of one or more of thebromodomain-containing proteins, such as BRD2, BRD3, BRD4, and/or BRDT.Thus, in certain embodiments, the present invention provides a methodfor treating an bromodomain-containing protein-mediated disorder, suchas a BET-mediated, a BRD2-mediated, a BRD3-mediated, a BRD4-mediateddisorder, and/or a BRDT-mediated disorder comprising the step ofinhibiting a bromodomain-containing protein, such as a BET protein, suchas BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof, by administeringto a patient in need thereof a provided compound, or a pharmaceuticallyacceptable composition thereof.

As used herein, the terms “bromodomain-containing protein-mediated”,“BET-mediated”, “BRD2-mediated”, “BRD3-mediated”, “BRD4-mediated”,and/or “BRDT-mediated” disorders or conditions means any disease orother deleterious condition in which one or more of thebromodomain-containing proteins, such as BET proteins, such as BRD2,BRD3, BRD4 and/or BRDT, or a mutant thereof, are known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in which oneor more of the bromodomain-containing proteins, such as BET proteins,such as BRD2, BRD3, BRD4, and/or BRDT, or a mutant thereof, are known toplay a role.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer and otherproliferative disorders, inflammatory diseases, sepsis, autoimmunedisease, and viral infection. Thus one aspect is a method of treating asubject having a disease, disorder, or symptom thereof the methodincluding administration of a compound or composition herein to thesubject. In one embodiment, a human patient is treated with a compoundof the invention and a pharmaceutically acceptable carrier, adjuvant, orvehicle, wherein said compound is present in an amount to measurablyinhibit bromodomain-containing protein activity (such as BET protein,e.g., BRD2, BRD3, BRD4, and/or BRDT) in the patient.

The invention further relates to a method for treating or amelioratingcancer or another proliferative disorder by administration of aneffective amount of a compound according to this invention to a mammal,in particular a human in need of such treatment. In some aspects of theinvention, the disease to be treated by the methods of the presentinvention is cancer. Examples of cancers treated using the compounds andmethods described herein include, but are not limited to, adrenalcancer, acinic cell carcinoma, acoustic neuroma, acral lentiginousmelanoma, acrospiroma, acute eosinophilic leukemia, acute erythroidleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia,acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma,adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor,adenosquamous carcinoma, adipose tissue neoplasm, adrenocorticalcarcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia,AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft partsarcoma, ameloblastic fibroma, anaplastic large cell lymphoma,anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocyticleukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer,bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma insitu, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, primary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma,retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation,rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor,sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer,small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,somatostatinoma, soot wart, spinal tumor, splenic marginal zonelymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease,small intestine cancer, squamous carcinoma, stomach cancer, T-celllymphoma, testicular cancer, thecoma, thyroid cancer, transitional cellcarcinoma, throat cancer, urachal cancer, urogenital cancer, urothelialcarcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visualpathway glioma, vulvar cancer, vaginal cancer, Waldenstrom'smacroglobulinemia, Warthin's tumor, and Wilms' tumor.

In some embodiments, the present invention provides a method of treatinga benign proliferative disorder. Such benign proliferative disordersinclude, but are not limited to, benign soft tissue tumors, bone tumors,brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma,meningioma, multiple endocrine neoplasia, nasal polyps, pituitarytumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomachpolyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas,vocal cord nodules, polyps, and cysts, Castleman disease, chronicpilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, andjuvenile polyposis syndrome.

The invention further relates to a method for treating infectious andnoninfectious inflammatory events and autoimmune and other inflammatorydiseases by administration of an effective amount of a provided compoundto a mammal, in particular a human in need of such treatment. Examplesof autoimmune and inflammatory diseases, disorders, and syndromestreated using the compounds and methods described herein includeinflammatory pelvic disease, urethritis, skin sunburn, sinusitis,pneumonitis, encephalitis, meningitis, myocarditis, nephritis,osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis,gingivitis, appendicitis, pancreatitis, cholecystitis,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, Type Idiabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoidarthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis,chronic idiopathic thrombocytopenic purpura, Waldenstrommacroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopicdermatitis, degenerative joint disease, vitiligo, autoimmunehypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleracierma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In some embodiments, the present invention provides a method of treatingsystemic inflammatory response syndromes such as LPS-induced endotoxicshock and/or bacteria-induced sepsis by administration of an effectiveamount of a provided compound to a mammal, in particular a human in needof such treatment.

The invention further relates to a method for treating viral infectionsand diseases by administration of an effective amount of a providedcompound to a mammal, in particular a human in need of such treatment.Examples of viral infections and diseases treated using the compoundsand methods described herein include episome-based DNA virusesincluding, but not limited to, human papillomavirus, Herpesvirus,Epstein-Barr virus, human immunodeficiency virus, hepatis B virus, andhepatitis C virus.

The invention further provides a method of treating a subject, such as ahuman, suffering from one of the abovementioned conditions, illnesses,disorders or diseases. The method comprises administering atherapeutically effective amount of one or more provided compounds,which function by inhibiting a bromodomain and, in general, bymodulating gene expression, to induce various cellular effects, inparticular induction or repression of gene expression, arresting cellproliferation, inducing cell differentiation and/or inducing apoptosis,to a subject in need of such treatment.

The invention further provides a therapeutic method of modulatingprotein methylation, gene expression, cell proliferation, celldifferentiation and/or apoptosis in vivo in diseases mentioned above, inparticular cancer, inflammatory disease, and/or viral disease comprisingadministering to a subject in need of such therapy a pharmacologicallyactive and therapeutically effective amount of one or more providedcompounds.

The invention further provides a method of regulating endogenous orheterologous promoter activity by contacting a cell with a providedcompound.

In certain embodiments, the invention provides a method of treating adisorder (as described above) in a subject, comprising administering tothe subject identified as in need thereof, a compound of the invention.The identification of those patients who are in need of treatment forthe disorders described above is well within the ability and knowledgeof one skilled in the art. Certain of the methods for identification ofpatients which are at risk of developing the above disorders which canbe treated by the subject method are appreciated in the medical arts,such as family history, and the presence of risk factors associated withthe development of that disease state in the subject patient. Aclinician skilled in the art can readily identify such candidatepatients, by the use of, for example, clinical tests, physicalexamination and medical/family history.

A method of assessing the efficacy of a treatment in a subject includesdetermining the pre-treatment extent of a disorder by methods well knownin the art (e.g., determining tumor size or screening for tumor markerswhere the cell proliferative disorder is cancer) and then administeringa therapeutically effective amount of a compound of the invention, tothe subject. After an appropriate period of time after theadministration of the compound (e.g., 1 day, 1 week, 2 weeks, one month,six months), the extent of the disorder is determined again. Themodulation (e.g., decrease) of the extent or invasiveness of thedisorder indicates efficacy of the treatment. The extent or invasivenessof the disorder may be determined periodically throughout treatment. Forexample, the extent or invasiveness of the disorder may be checked everyfew hours, days or weeks to assess the further efficacy of thetreatment. A decrease in extent or invasiveness of the disorderindicates that the treatment is efficacious. The method described may beused to screen or select patients that may benefit from treatment with acompound of the invention.

The invention further relates to the use of provided compounds for theproduction of pharmaceutical compositions which are employed for thetreatment and/or prophylaxis and/or amelioration of the diseases,disorders, illnesses and/or conditions as mentioned herein.

The invention further relates to the use of provided compounds for theproduction of pharmaceutical compositions which are employed for thetreatment and/or prophylaxis of diseases and/or disorders responsive orsensitive to the inhibition of bromodomain-containing proteins,particularly those diseases mentioned above, such as e.g. cancer,inflammatory disease, viral disease.

Another object of the present invention is the use of a compound asdescribed herein (e.g., of any formulae herein) in the manufacture of amedicament for use in the treatment of a disorder or disease herein.Another object of the present invention is the use of a compound asdescribed herein (e.g., of any formulae herein) for use in the treatmentof a disorder or disease herein.

Compounds or compositions described herein may be administered using anyamount and any route of administration effective for treating orlessening the severity of cancer or other proliferative disorder. Theexact amount required will vary from subject to subject, depending onthe species, age, and general condition of the subject, the severity ofthe infection, the particular agent, its mode of administration, and thelike. Provided compounds are preferably formulated in unit dosage formfor ease of administration and uniformity of dosage. The expression“unit dosage form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present disclosure will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

Pharmaceutically acceptable compositions of this disclosure can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, provided compounds may be administered orally orparenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg andpreferably from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

According to some embodiments, the invention relates to a method ofinhibiting bromodomain-containing proteins in a biological samplecomprising the step of contacting said biological sample with a providedcompound, or a composition thereof.

According to some embodiments, the invention relates to a method ofinhibiting a bromodomain-containing protein, such as a BET protein, suchas BRD2, BRD3, BRD4 and/or BRDT, or a mutant thereof, activity in abiological sample comprising the step of contacting said biologicalsample with a provided compound, or a composition thereof.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of activity of an protein, e.g., a bromodomain-containingprotein, such as a BET protein, such as BRD2, BRD3, BRD4 and/or BRDT, ora mutant thereof, in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

According to another embodiment, the invention relates to a method ofinhibiting activity of one or more bromodomain-containing protein, suchas a BET protein, such as BRD2, BRD3, BRD4, and/or BRDT, or a mutantthereof, in a patient comprising the step of administering to saidpatient a provided compound, or a composition comprising said compound.In certain embodiments, the present invention provides a method fortreating a disorder mediated by one or more bromodomain-containingproteins, such as a BET protein, such as BRD2, BRD3, BRD4, and/or BRDT,or a mutant thereof, in a patient in need thereof, comprising the stepof administering to said patient a provided compound or pharmaceuticallyacceptable composition thereof. Such disorders are described in detailherein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition may also be present in the compositions of thisdisclosure or administered separately as a part of a dosage regimen. Asused herein, additional therapeutic agents that are normallyadministered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated.”

In some embodiments, the additional therapeutic agent is an epigeneticdrug. As used herein, the term “epigenetic drug” refers to a therapeuticagent that targets an epigenetic regulator. Examples of epigeneticregulators include the histone lysine methyltransferases, histonearginine methyl transferases, histone demethylases, histonedeacetylases, histone acetylases, and DNA methyltransferases. Histonedeacetylase inhibitors include, but are not limited to, vorinostat.

Other therapies, chemotherapeutic agents, or other anti-proliferativeagents may be combined with a provided compound to treat proliferativediseases and cancer. Examples of therapies or anticancer agents that maybe used in combination with compounds of formula I include surgery,radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes), endocrine therapy, a biologic response modifier(e.g., an interferon, an interleukin, tumor necrosis factor (TNF),hyperthermia and cryotherapy, an agent to attenuate any adverse effects(e.g., an antiemetic), and any other approved chemotherapeutic drug.

A provided compound may also be used to advantage in combination withone or more antiproliferative compounds. Such antiproliferativecompounds include an aromatase inhibitor; an anti-estrogen; ananti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; atopoisomerase II inhibitor; a microtubule active agent; an alkylatingagent; a retinoid, a carotenoid, or a tocopherol; a cyclooxygenaseinhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; aplatin compound; a methionine aminopeptidase inhibitor; abisphosphonate; an antiproliferative antibody; a heparanase inhibitor;an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; aproteasome inhibitor; a compound used in the treatment of hematologicmalignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindleprotein inhibitor; a MEK inhibitor; an antitumor antibiotic; anitrosourea; a compound targeting/decreasing protein or lipid kinaseactivity, a compound targeting/decreasing protein or lipid phosphataseactivity, or any further anti-angiogenic compound.

Exemplary aromatase inhibitors include steroids, such as atamestane,exemestane and formestane, and non-steroids, such as aminoglutethimide,rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole,vorozole, fadrozole, anastrozole and letrozole.

Exemplary anti-estrogens include tamoxifen, fulvestrant, raloxifene andraloxifene hydrochloride. Anti-androgens include, but are not limitedto, bicalutamide. Gonadorelin agonists include, but are not limited to,abarelix, goserelin and goserelin acetate.

Exemplary topoisomerase I inhibitors include topotecan, gimatecan,irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148. Topoisomerase IIinhibitors include, but are not limited to, the anthracyclines such asdoxorubicin, daunorubicin, epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinsetoposide and teniposide.

Exemplary microtubule active agents include microtubule stabilizing,microtubule destabilizing compounds and microtubulin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;colchicine and epothilones and derivatives thereof.

Exemplary alkylating agents include cyclophosphamide, ifosfamide,melphalan or nitrosoureas such as carmustine and lomustine.

Exemplary cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkylsubstituted 2-arylaminophenylacetic acid and derivatives, such ascelecoxib, rofecoxib, etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

Exemplary matrix metalloproteinase inhibitors (“MMP inhibitors”) includecollagen peptidomimetic and non-peptidomimetic inhibitors, tetracyclinederivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251,BAY 12-9566, TAA211, MMI270B, and AAJ996.

Exemplary mTOR inhibitors include compounds that inhibit the mammaliantarget of rapamycin (mTOR) and possess antiproliferative activity suchas sirolimus, everolimus, CCI-779, and ABT578.

Exemplary antimetabolites include 5-fluorouracil (5-FU), capecitabine,gemcitabine, DNA demethylating compounds, such as 5-azacytidine anddecitabine, methotrexate and edatrexate, and folic acid antagonists suchas pemetrexed.

Exemplary platin compounds include carboplatin, cis-platin, cisplatinum,and oxaliplatin.

Exemplary methionine aminopeptidase inhibitors include bengamide or aderivative thereof and PPI-2458.

Exemplary bisphosphonates include etidronic acid, clodronic acid,tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid,risedronic acid and zoledronic acid.

Exemplary antiproliferative antibodies include trastuzumab,trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PRO64553, and 2C4.The term “antibody” is meant to include intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least twointact antibodies, and antibody fragments, so long as they exhibit thedesired biological activity.

Exemplary heparanase inhibitors include compounds that target, decreaseor inhibit heparin sulfate degradation, such as PI-88 and OGT2115.

The term “an inhibitor of Ras oncogenic isoforms,” such as H-Ras, K-Ras,or N-Ras, as used herein refers to a compound which targets, decreases,or inhibits the oncogenic activity of Ras; for example, a farnesyltransferase inhibitor such as L-744832, DK8G557, tipifarnib, andlonafarnib.

Exemplary telomerase inhibitors include compounds that target, decreaseor inhibit the activity of telomerase, such as compounds which inhibitthe telomerase receptor, such as telomestatin.

Exemplary proteasome inhibitors include compounds that target, decreaseor inhibit the activity of the proteasome including, but not limited to,bortezomib.

The phrase “compounds used in the treatment of hematologic malignancies”as used herein includes FMS-like tyrosine kinase inhibitors, which arecompounds targeting, decreasing or inhibiting the activity of FMS-liketyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and busulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Exemplary Flt-3 inhibitors include PKC412, midostaurin, a staurosporinederivative, SU11248 and MLN518.

Exemplary HSP90 inhibitors include compounds targeting, decreasing orinhibiting the intrinsic ATPase activity of HSP90; degrading, targeting,decreasing or inhibiting the HSP90 client proteins via the ubiquitinproteosome pathway. Compounds targeting, decreasing or inhibiting theintrinsic ATPase activity of HSP90 are especially compounds, proteins orantibodies which inhibit the ATPase activity of HSP90, such as17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycinderivative; other geldanamycin related compounds; radicicol and HDACinhibitors.

The phrase “a compound targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or any furtheranti-angiogenic compound” as used herein includes a protein tyrosinekinase and/or serine and/or threonine kinase inhibitor or lipid kinaseinhibitor, such as a) a compound targeting, decreasing or inhibiting theactivity of the platelet-derived growth factor-receptors (PDGFR), suchas a compound which targets, decreases, or inhibits the activity ofPDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such asimatinib, SU101, SU6668 and GFB-111; b) a compound targeting, decreasingor inhibiting the activity of the fibroblast growth factor-receptors(FGFR); c) a compound targeting, decreasing or inhibiting the activityof the insulin-like growth factor receptor I (IGF-IR), such as acompound which targets, decreases, or inhibits the activity of IGF-IR;d) a compound targeting, decreasing or inhibiting the activity of theTrk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) acompound targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family; f) a compound targeting, decreasing orinhibiting the activity of the Ret receptor tyrosine kinase; g) acompound targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, such as imatinib; h) a compoundtargeting, decreasing or inhibiting the activity of the c-Kit receptortyrosine kinases, such as imatinib; i) a compound targeting, decreasingor inhibiting the activity of members of the c-Abl family, theirgene-fusion products (e.g. Bcr-Abl kinase) and mutants, such as anN-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib;PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compoundtargeting, decreasing or inhibiting the activity of members of theprotein kinase C (PKC) and Raf family of serine/threonine kinases,members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK familymembers, and/or members of the cyclin-dependent kinase family (CDK),such as a staurosporine derivative disclosed in U.S. Pat. No. 5,093,330,such as midostaurin; examples of further compounds include UCN-01,safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220and RO 320432; GO 6976; ISIS 3521; LY333531/LY379196; a isochinolinecompound; a farnesyl transferase inhibitor; PD184352 or QAN697, orAT7519; k) a compound targeting, decreasing or inhibiting the activityof a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) a compound targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180;trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, CI-1033, EKB-569,GW-2016, antibodies E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 andE7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compoundtargeting, decreasing or inhibiting the activity of the c-Met receptor.

Exemplary compounds that target, decrease or inhibit the activity of aprotein or lipid phosphatase include inhibitors of phosphatase 1,phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity unrelated to protein or lipid kinaseinhibition, e.g. thalidomide and TNP-470.

Additional exemplary chemotherapeutic compounds, one or more of whichmay be used in combination with provided compounds, include:daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone,idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabinephosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine,6-mercaptopurine, pentostatin, hydroxyurea,2-hydroxy-1H-isoindole-1,3-dione derivatives,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate,angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474,SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugen; FLT-4 inhibitors,FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimersodium, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol,cortexolone, 17α-hydroxyprogesterone, corticosterone,desoxycorticosterone, testosterone, estrone, dexamethasone,fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, abiological response modifier, such as a lymphokine or interferon, anantisense oligonucleotide or oligonucleotide derivative, shRNA or siRNA,or a miscellaneous compound or compound with other or unknown mechanismof action.

For a more comprehensive discussion of updated cancer therapies see, TheMerck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference. See also the National Cancer Institute(CNI) website (www.nci.nih.gov) and the Food and Drug Administration(FDA) website for a list of the FDA approved oncology drugs.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, a TNF blocker, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; animmunomodulatory agent, including immunosuppressive agents, such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, aninterferon, a corticosteroid, cyclophosphamide, azathioprine, andsulfasalazine; a neurotrophic factor such as an acetylcholinesteraseinhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ionchannel blocker, riluzole, or an anti-Parkinson's agent; an agent fortreating cardiovascular disease such as a beta-blocker, an ACEinhibitor, a diuretic, a nitrate, a calcium channel blocker, or astatin; an agent for treating liver disease such as a corticosteroid,cholestyramine, an interferon, and an anti-viral agent; an agent fortreating blood disorders such as a corticosteroid, an anti-leukemicagent, or a growth factor; or an agent for treating immunodeficiencydisorders such as gamma globulin.

The above-mentioned compounds, one or more of which can be used incombination with a provided compound, can be prepared and administeredas described in the art.

Provided compounds can be administered alone or in combination with oneor more other therapeutic compounds, possible combination therapy takingthe form of fixed combinations or the administration of a providedcompound and one or more other therapeutic compounds being staggered orgiven independently of one another, or the combined administration offixed combinations and one or more other therapeutic compounds. Providedcompounds can besides or in addition be administered especially fortumor therapy in combination with chemotherapy, radiotherapy,immunotherapy, phototherapy, surgical intervention, or a combination ofthese. Long-term therapy is equally possible as is adjuvant therapy inthe context of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Such additional agents may be administered separately from a compositioncontaining a provided compound, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a provided compound in a single composition. Ifadministered as part of a multiple dosage regimen, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. In oneembodiment, treatment regimens according to the present inventioncomprise administration to a patient in need of such treatment fromabout 10 mg to about 1000 mg of the compound(s) of this invention perday in single or multiple doses.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a providedcompound may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, an embodiment of theinvention provides a single unit dosage form comprising a providedcompound, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle for use in the methods of theinvention.

The amount of both, a provided compound and additional therapeutic agent(in those compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Preferably, compositionsshould be formulated such that a dosage of between 0.01-100 mg/kg bodyweight/day of a provided compound can be administered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the provided compound may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent. In such compositions a dosage ofbetween 0.01-1,000 μg/kg body weight/day of the additional therapeuticagent can be administered.

The amount of additional therapeutic agent present in the compositionsof this disclosure will be no more than the amount that would normallybe administered in a composition comprising that therapeutic agent asthe only active agent. Preferably the amount of additional therapeuticagent in the presently disclosed compositions will range from about 50%to 100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Provided compounds, or pharmaceutical compositions thereof, may also beincorporated into compositions for coating an implantable medicaldevice, such as prostheses, artificial valves, vascular grafts, stentsand catheters. Vascular stents, for example, have been used to overcomerestenosis (re-narrowing of the vessel wall after injury). However,patients using stents or other implantable devices risk clot formationor platelet activation. These unwanted effects may be prevented ormitigated by pre-coating the device with a pharmaceutically acceptablecomposition comprising a provided compound. Implantable devices coatedwith a compound of this invention are another embodiment of the presentinvention.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Therecitation of an embodiment herein includes that embodiment as anysingle embodiment or in combination with any other embodiments orportions thereof.

In another aspect, the invention provides a method of method ofsynthesizing a compound of formula I. Another embodiment is a method ofmaking a compound of any of the formulae herein using any one, orcombination of, reactions delineated herein. The method can include theuse of one or more intermediates or chemical reagents delineated herein.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Example 1 Synthesis of (2-Bromphenyl)(4-Chlorophenyl)Methanone

To a solution of 2-bromobenzaldehyde (3.15 mL, 27.0 mmol) and THF (135mL) at 0° C. was added (4-chlorophenyl)magnesium bromide solution (29.7mL, 1M in THF, 29.7 mmol). The reaction was stirred at 0° C. for 30 minbefore addition of a saturated solution of ammonium chloride. The layerswere separated and the aqueous extracted with EtOAc. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage to afford(2-bromophenyl)(4-chlorophenyl)methanol. To a solution of DCM (100 mL)and oxalyl chloride (2.471 mL, 28.2 mmol) at −78° C. was added DMSO(3.34 mL, 47.0 mmol) and the reaction stirred at −78° C. for 15 min.After 15 min a solution of (2-bromophenyl)(4-chlorophenyl)methanol inDCM (25 mL) was added dropwise and stirred for 15 min at −78° C. beforeaddition of Et₃N (9.84 mL, 70.6 mmol). The cold bath was removed and thereaction was warmed to room temperature. To this solution was addedwater and the layers separated. The aqueous was extracted with DCM andthe combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage (EtOAc/hex) toafford (2-bromophenyl)(4-chlorophenyl)methanone. LC/MS m/z 295 [M+H]⁺.

Example 2 Synthesis of prop-2-yn-1-yl benzoate

To a solution of prop-2-yn-1-ol (3.63 mL, 62.4 mmol), DCM (180 mL), andEt₃N (17.40 mL, 125 mmol) at 0° C. were added benzoyl chloride (7.25 mL,62.4 mmol) and DMAP (0.381 g, 3.12 mmol). The reaction was stirred whilewarming to room temperature overnight. The reaction was diluted withwater and the layers separated. The aqueous was extracted with DCM andthe combined organics were dried over Na₂SO₄, filtered, and concentratedto afford prop-2-yn-1-yl benzoate which was used in subsequent reactionswithout further purification. LC/MS m/z 161 [M+H]⁺.

Example 3 Synthesis of (3-methylisoxazol-5-yl)methyl benzoate

To a solution of chloroform, Et₃N (0.435 mL, 3.12 mmol), prop-2-ynylbenzoate (1 g, 6.24 mmol), and (E)-acetaldehyde oxime (0.571 mL, 9.37mmol) at 0° C. was added bleach (23.12 mL, 18.73 mmol). The reaction wasstirred overnight before the layers were separated and the aqueousextracted with DCM. The combined organics were dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified via Biotage(EtOAc/hex) to afford (3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z218 [M+H]⁺.

Example 4 Synthesis of (4-bromo-3-methylisoxazol-5-yl)methyl benzoate

To a resealable vial was added (3-methylisoxazol-5-yl)methyl benzoate(907 mg, 4.18 mmol), AcOH (3.5 mL, 61.1 mmol), and NBS (892 mg, 5.01mmol). The reaction was heated to 110° C. overnight. The reaction wascooled to room temperature and diluted with water. The aqueous wasextracted with EtOAc and the combined organics were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude residue waspurified via Biotage (EtOAc/hex) to afford(4-bromo-3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 296 [M+H]⁺.

Example 5 Synthesis of(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate

To a resealable vial was added Pd(OAc)₂ (3.87 mg, 0.017 mmol) and X-phos(16.42 mg, 0.034 mmol) before the vial was sealed and evacuated andpurged with N₂ (3×). To this vial was added(4-bromo-3-methylisoxazol-5-yl)methyl benzoate (102 mg, 0.344 mmol) indioxane (1 mL), Et₃N (144 μl, 1.033 mmol), and4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution (517 μl, 1M in THF,0.517 mmol). The reaction was stirred overnight at 80° C., cooled toroom temperature and filtered. The filtrate was concentrated to affordcrude(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methylbenzoate. To a resealable vial was added K₂CO₃ (47.5 mg, 0.344 mmol),PdCl₂(dppf)-CH₂Cl₂ Adduct (20.06 mg, 0.025 mmol),(2-bromophenyl)(4-chlorophenyl)methanone (72.6 mg, 0.246 mmol). The vialwas sealed and evacuated and purged with N₂ (3×) before addition ofcrude(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methylbenzoate (118 mg, 0.344 mmol) dissolved in dioxane (2 mL). Water (0.5mL) was then added to this solution before the vial was heated to 110°C. overnight. The reaction was cooled to room temperature, diluted withEtOAc, filtered, and concentrated. The crude residue was purified viaBiotage (EtOAc/hex) to afford(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate.LC/MS m/z 432 [M+H]⁺.

Example 6 Synthesis of6-(4-chlorophenyl)-1-methyl-4,1-benzo[c]isoxazolo[4,5-e]azepine

(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone.

To a round bottomed flask was added(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate(32.7 mg, 0.076 mmol), THF (3 mL), MeOH (3 mL), and water (1.5 mL). Thissolution was cooled to 0° C. before addition of Lithium HydroxideMonohydrate (9.53 mg, 0.227 mmol) and the reaction stirred at 0° C. for1 h before diluting with water and EtOAc. The layers were separated andthe aqueous extracted with EtOAc (3×). The combined organics were washedwith brine, dried over Na₂SO₄, filtered, and concentrated to affordcrude(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone.

(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylmethanesulfonate.

To a round bottomed flask was added crude(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone(24.9 mg, 0.076 mmol), DCM (2 mL), and Et₃N (21.18 μl, 0.152 mmol). Thissolution was cooled to 0° C. before addition of MsCl (7.10 μl, 0.091mmol) and the reaction stirred at 0° C. for 30 min before diluting withwater and extracting with DCM. The combined organics were dried overNa₂SO₄, filtered, and concentrated to afford crude(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylmethanesulfonate.

(2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone.

To a round bottomed flask was added crude(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylmethanesulfonate (30.8 mg, 0.076 mmol), DMF (2 mL), and sodium azide(4.93 mg, 0.076 mmol). The reaction was stirred at room temperature for2 h before diluting with water and extracting with EtOAc. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford crude(2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone.

6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine (Compound190).

To a resealable vial was added crude(2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (27 mg, 0.077 mmol) and toluene. The vial wassealed and placed under N₂ before addition of trimethylphosphinesolution (92 μl, 1 M toluene, 0.092 mmol). The reaction was stirred atroom temperature for 2 h before purifying via Biotage (10 g, EtOAc/hex)to afford6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine. ¹H NMR(400 MHz, Acetone) δ 7.78-7.84 (m, 1H), 7.65-7.74 (m, 1H), 7.34-7.47 (m,6H), 4.62 (br. s, 2H), 2.54 (s, 3H). LC/MS m/z 309 [M+H]⁺.

Example 7 Synthesis of3-(((4-methoxybenzyl)oxy)methyl)-5-methylisoxazole

To a resealable vial were added NaH (193 mg, 60% dispersion in mineraloil, 4.82 mmol) and THF. The vial was cooled to 0° C. before addition of(4-methoxyphenyl)methanol (639 μl, 5.14 mmol) and the reaction stirredat 0° C. for 30 min before addition of3-(chloromethyl)-5-methylisoxazole (423 mg, 3.22 mmol) andtetrabutylammonium iodide (119 mg, 0.322 mmol). The reaction was heatedto reflux overnight. The vial was cooled to room temperature beforebeing diluted with ammonium chloride solution. The aqueous was extractedwith EtOAc and the combined organics were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude residue was purified viaBiotage (EtOAc/hex) to afford3-((4-methoxybenzyloxy)methyl)-5-methylisoxazole. LC/MS m/z 256 [M+Na]⁺.

Example 8 Synthesis of2-(3-(((4-methoxybenzyl)oxy)methyl)-5-methylisoxazol-4-yl)benzonitrile

To a resealable vial was added potassium acetate (112 mg, 1.143 mmol),palladium(II) chloride (0.507 mg, 2.86 μmol), and 2-bromobenzonitrile(104 mg, 0.572 mmol). The vial was sealed and evacuated and purged withN₂ (3×) before addition of DMA (4 mL) and3-((4-methoxybenzyloxy)methyl)-5-methylisoxazole (200 mg, 0.857 mmol).The vial was heated to 130° C. overnight. The reaction was cooled toroom temperature and diluted with water. The aqueous was extracted withEtOAc and the combined organics were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude residue was purified viaBiotage (EtOAc/hex) to afford2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzonitrile.LC/MS m/z 335 [M+H]⁺.

Example 9 Synthesis of2-(3-(((4-methoxybenzyl)oxy)methyl)-5-methylisoxazol-4-yl)benzaldehyde

To a round bottomed flask was added2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzonitrile(165.3 mg, 0.494 mmol) and DCM (3 mL). This solution was cooled to 0° C.before addition of a solution of DIBAL-H (593 μl, 1M in DCM, 0.593mmol). The reaction was stirred at 0° C. for 1 h before addition of 1NHCl. The layers were separated and the aqueous was extracted with DCM(3×). The combined organics were washed with 1N HCl and brine beforebeing dried over Na₂SO₄, filtered, and concentrated. The crude residuewas purified via Biotage (EtOAc/hex) to afford2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzaldehyde.LC/MS m/z 338 [M+H]⁺.

Example 10 Synthesis of(4-chlorophenyl)(2-(3-(((4-methoxybenzyl)oxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanol

To a round bottomed flask was added2-(3-(((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzaldehyde(94 mg, 0.279 mmol) and THF. The solution was cooled to −78° C. beforeaddition of (4-chlorophenyl)magnesium bromide solution (418 μl, 1M inTHF, 0.418 mmol) and the reaction stirred at −78° C. for 30 min. Thesolution was quenched via the addition of water and warmed to roomtemperature. The aqueous was extracted with EtOAc (3×) and the combinedorganics were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage (EtOAc/hex) toafford(4-chlorophenyl)(2-(3-(((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanol.LC/MS m/z 450 [M+H]⁺.

Example 11 Synthesis of(4-chlorophenyl)(2-(3-(((4-methoxybenzyl)oxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanone

To a round bottomed flask was added DCM (4 mL) and oxalyl chloride (28.0μl, 0.320 mmol) before the solution was cooled to −78° C. To thissolution was added DMSO (37.9 μl, 0.533 mmol) and the reaction stirredat −78° C. for 15 min before addition of(4-chlorophenyl)(2-(3-(((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanol(120 mg, 0.267 mmol) dissolved in DCM. The solution was stirred for anadditional 15 min before addition of Et₃N (112 μl, 0.800 mmol) and thereaction warmed to room temperature. Water was added and the layersseparated. The aqueous was extracted with DCM and the combined organicswere dried over Na₂SO₄, filtered, and concentrated. The crude residuewas purified via Biotage (EtOAc/hex) to afford(4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanone.LC/MS m/z 448 [M+H]⁺.

Example 12 Synthesis of(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone

To a round bottomed flask was added(4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanone (69 mg, 0.154 mmol), DCM, and water. This solution was cooled to 0°C. before addition of DDQ (69.9 mg, 0.308 mmol) and the reaction stirredat 0° C. for 4 h before addition of NaHCO₃ solution. The layers wereseparated and the aqueous extracted with DCM. The combined organics weredried over Na₂SO₄, filtered, and concentrated. The crude residue waspurified via Biotage (EtOAc/hex) to afford(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone.LC/MS m/z 328 [M+H]⁺.

Example 13 Synthesis of6-(4-chlorophenyl)-1-methyl-4,1-benzo[c]isoxazolo[4,3-e]azepine(Compound 191)

To a round bottomed flask was added(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone(47.2 mg, 0.144 mmol), DCM, and Et₃N (40.1 μl, 0.288 mmol). The solutionwas cooled to 0° C. before addition of Ms-Cl (13.47 μl, 0.173 mmol). Thereaction was stirred at 0° C. for 30 min before addition of water. Thelayers were separated and the aqueous was extracted with DCM. Thecombined organics were dried over Na₂SO₄, filtered, and concentrated toafford crude (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methylmethanesulfonate. To a round bottomed flask was added(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methylmethanesulfonate (58.4 mg, 0.144 mmol), DMF, and sodium azide (28.1 mg,0.432 mmol). The reaction was stirred at room temperature for 2 h beforediluting with water and extracting the aqueous with EtOAc. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford crude(2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone. To a round bottomed flask was added(2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone(50.8 mg, 0.144 mmol), toluene (3 mL), and trimethylphosphine solution(216 μl, 1M in toluene, 0.216 mmol). The reaction was stirred at roomtemperature over 2 days before purifying via Biotage (EtOAc/hex) toafford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepine.LC/MS m/z 309 [M+H]⁺; ¹H NMR (400 MHz, Acetone) δ 7.70-7.76 (m, 1H),7.63-7.70 (m, 1H), 7.32-7.49 (m, 6H), 5.10 (br. s, 1H), 4.10 (br. s,1H), 2.68 (s, 3H).

Example 14 General Synthetic Approach to Compounds of Formula I, WhereinR₂ is Hydrogen and R₃ is —CH₂—C(O)—N(R′)(R″)

Scheme 1 sets forth a general method for making certain compounds of theinvention.

One example of a halo-ester 10 was synthesized as described below.

Methyl 2-bromo-4,5-dimethylthiophene-3-carboxylate.

To a solution of methyl 4,5-dimethylthiophene-3-carboxylate (1.89 g,11.10 mmol) in DMF (10 mL) was added N-bromosuccinimide (2.37 g, 13.32mmol) at room temperature. The reaction mixture turned orange over timeand was allowed to stir for 2 h, at which time LC-MS analysis indicatedcomplete consumption of the methyl 4,5-dimethylthiophene-3-carboxylate.To the solution was added MTBE and water. The aqueous layer wasextracted with MTBE (2×), the combined orange organic layer was washedwith 1% sodium thiosulfate, followed by water (2×). The organic phasewas dried over Na₂SO₄ and concentrated to give yellow oil. The crudereaction mixture was purified on Biotage system (isocratic elution 2%EtOAc:98% Hexanes) to give the titled compound as a light yellow solid(2.61 g, 10.5 mmol, 94% yield). LC/MS m/z 249 [M+H]⁺.

One example of the borolane reagent 11 was synthesized as describedbelow.

(3-Methylisoxazol-5-yl)methyl acetate.

To a suspension of N-chlorosuccimide (71.5 g, 535 mmol) in CHCl₃ (360mL) and pyridine (1.61 g, 20.3 mmol) was added a solution of(E)-acetaldehyde oxime (31.6 g, 535 mmol). After a period of 1 h,propargylacetate (35.0 g, 357 mmol) in a minimum of CHCl₃ was added tothe previous mixture. Triethylamine (114 g, 1124 mmol) was then addeddropwise and the reaction mixture was cooled in a water bath in order tomaintain the internal temperature below the boiling point. After aperiod of 1 h, the reaction mixture was concentrated in vacuo followedby the addition of EtOAc. The mixture was filtered on a glass filter andthe solid washed with EtOAc, the combined filtrates were evaporated.After evaporation, additional EtOAc was added and the previous processrepeated. The EtOAc was evaporated and the crude product was purified ona on Biotage system (isocratic elution 40% EtOAc:60% Hexanes) and thefractions followed by LC/MS to provide the titled compound as a clearoil. LC/MS m/z 156 [M+H]⁺.

(4-Bromo-3-methylisoxazol-5-yl)methyl acetate

To a solution of (3-methylisoxazol-5-yl)methyl acetate (0.979 g, 6.31mmol) in AcOH (10 mL, 175 mmol) was added N-bromosuccinimide (1.30 g,7.30 mmol) and H₂SO₄ (0.65 mL, 12.19 mmol). The reaction was heated to110° C. After 1 h, the reaction mixture was cooled to room temperatureand carefully poured into a beaker containing ice and saturated NaHCO₃.The bi-phasic was vigorously stirred and basic solution (pH ˜8-9) wasextracted with EtOAc (2×15 mL). The organic layer was washed with 2%sodium thiosulfate, washed with brine (20 mL), dried over Na₂SO₄, andconcentrated to give a light yellow oil. The oil was purified on Biotagesystem (isocratic elution 10% EtOAc:90% Hexanes) to give the titledcompound (1.30 g, 5.55 mmol, 88% Yield) as a colorless yellow oil. LC/MSm/z 234 [M+H]⁺.

(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methylacetate.

To a 500 mL flask (under N₂ (g)) was addeddichlorobis(acetonitrile)palladium(II) (0.551 g, 2.12 mmol) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.50 g, 8.53 mmol).To the solids were sequentially added a solution of(4-bromo-3-methylisoxazol-5-yl)methyl acetate (24.8 g, 106 mmol) in1,4-dioxane (65 mL), Et₃N (44.3 mL, 318 mmol), and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 mL, 160 mmol). The flask wassequentially evacuated and purged under N₂, and this process wasrepeated three times. The reaction mixture was heated to 110° C. (undera constant stream of N₂ (g)) and allowed to stir for ˜4 h. LC-MSanalysis at this point showed complete conversion of the startingbromo-isoxazole. The reaction mixture was cooled to room temperature andEtOAc (100 mL) was added. After 15 min of stirring, the suspension wasfiltered over a pad of Celite. The filter cake was washed with EtOAc(3×100 mL), concentrated in vacuo, and the solvent was switched using1,4-Dioxane (2×50 mL). The borate ester with used without furtherpurification.

Suzuki Couplings to Produce Intermediate 12

Protocol I: Coupling Under Anhydrous Conditions

A solution of the borolane reagent (11; 1.6 equivalents) in 1,4-dioxane(1.6 M) was added to Pd₂(dba)₃ (˜2 mol %), anhydrous K₃PO₄ (tribasic)(2.0 equivalents), anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (˜4 mol %) under N₂(g). After stirring the suspension for 2 min., a solution of halo-ester(10; 1.0 equivalents) in MeOH (0.3 M) was introduced in one portion. Thesuspension was evacuated and purged with N₂ (3×), and subsequentlyheated to 67° C. for 1 h. The reaction mixture was cooled to roomtemperature and filtered through a plug of Celite. The filter cake waswashed with MeOH (3×). The filtrate was concentrated to give a brownoil. The resultant oil was concentrated from MeOH several times (3×) toaid in cleavage of the acetyl ester and produced the alcohol. The crudereaction mixture was purified on Biotage system (generally gradientelution 5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, then isocratic30% EtOAc:70% Hexanes) to give the titled compound (typically in 80%-93%yield).

Protocol II: Coupling Under Bi-Phasic Conditions

To a round bottomed flask was added PdCl₂(dppf)-CH₂Cl₂ adduct (˜5 mol %)and potassium carbonate (2 equivalents) before the flask was evacuatedand backfilled with N₂ (3×). To this flask was added borolane reagent 11(such as3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methylacetate (typically 1.5-2 equivalents) dissolved in dioxane (typically˜0.3-0.5 M), the appropriate halo-ester 10 (1 equivalent) and water. Thesolution was heated to reflux until LC-MS analysis indicated completeconsumption of starting material (typically 2-4 h). The reaction wascooled to room temperature and diluted with water and EtOAc. The layerswere separated and the aqueous phase was extracted with EtOAc. Thecombined organics were washed with water and brine, before being driedover Na₂SO₄, filtered, and concentrated. The crude residue was taken upMeOH (typically ˜0.3 M) and sodium methoxide was added (0.2equivalents). The reaction was stirred at room temperature until LC-MSanalysis indicated complete consumption of starting material. Thereaction was diluted with water and EtOAc. The layers were separated andthe aqueous phase extracted with EtOAc (3×). The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude residue was purified via Biotage (EtOAc/hex) to afford the alcohol(typically 40-80% yield).

General Protocol to Produce Intermediate 13.

a. Oxidation

To a round bottomed flask charged with anhydrous CH₂Cl₂ (typically 0.2 Min substrate) was added oxalyl chloride (2 equivalents) and the solutioncooled to −78° C. before dropwise addition of DMSO (4 equivalents;caution gas evolution). The solution was stirred at −78° C. for 15 minbefore dropwise addition of the alcohol dissolved in a minimal amount ofCH₂Cl₂. This solution was stirred for 15 min at −78° C. before additionof triethylamine (3-5 equivalents) and the solution warmed to roomtemperature. The reaction was poured into water and the layersseparated. The aqueous phase was extracted with CH₂Cl₂ and the combinedorganics were dried over Na₂SO₄, filtered, and concentrated. The cruderesidue was purified via Biotage (EtOAc/Hex) to afford the aldehyde(typically 60-90% yield).

b. (S)-tert-Butylsulfinylimine (Intermediate 13) Formation

To a round bottomed flask charged with aldehyde,(S)-2-methylpropane-2-sulfinamide (1.2 equivalents), and CH₂Cl₂(typically ˜0.2-0.5 M in substrate) was added tetraethoxytitanium (2equivalents). The solution was stirred overnight at room temperaturebefore addition of brine. This slurry was vigorously stirred for 30 minbefore filtering. The filter cake was washed with CH₂Cl₂. The layerswere separated and the aqueous phase was extracted with CH₂Cl₂. Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated. The crude residue was purified via Biotage (EtOAc/hex)to afford the sulfinamine (typically 60-90% yield).

General Protocol to Produce Intermediate 15

To a cooled (−8.5° C.) solution of the appropriate(S)-tert-butylsulfinylimine (1 equivalent) in N-methylpyrrolidinone(0.16 M) was added in a dropwise fashion a 0.5 M solution of reagent 14,e.g., 2-tert-butoxy-2-oxoethyl)zinc(II) chloride (2 equivalent) in Et₂Oover a period of 10 min. The yellow solution turned clear and colorless.The reaction temperature was maintained between −8.5° C. to 5° C. untilcomplete consumption of sulfinylimine was observed by LC-MS and TLC.After 4.5 h, saturated aqueous NH₄Cl and MTBE were introduced. Theaqueous layer turned thick and “gel-like”, at which point 1 N HCl wasadded. The aqueous layer was extracted with MTBE (2×). The combinedorganic layers were washed with saturated NaHCO₃, dried over Na₂SO₄, andconcentrated in vacuo. The mixture was purified on Biotage system(typically gradient elution 17% MTBE:83% Hexanes to 70% MTBE:30%Hexanes) to give the desired (S,S)-diastereomer (typically in 60%-69%yield). Partial separation of diastereomers was achieved duringpurification and successive chromatographic runs were performed tomaximize yield of major pure diastereomer. The undesired(S,R)-diastereomer was obtained is typically obtained in 10% yield.

General Protocol to Produce Intermediate 16

To a solution of methyl N-tert-butylsulfinyl amines (1 equivalent) inMeOH (˜0.16 M) was added a solution of 4 M HCl (1.6 equivalent) in1,4-dioxane. LC-MS analysis after 15 min indicated complete consumptionof the starting material. The solvent was evaporated and the excess HClwas azeotropically removed using heptane (2×), followed by THF to givethe appropriate chiral ammonium chloride (99% yield) as a white foamthat was used without further purification.

General Protocol to Produce Intermediate 17

To a cooled solution (−20° C.) of the appropriate chiral ammonium salt(1 equivalent) in THF (0.4 M) was introduced a solution of 2.9 Misopropylmagnesium bromide (4.22 equivalent) in2-methyl-tetrahydrofuran. After complete addition of the base, LC-MSanalysis indicated complete consumption of the ammonium salt. To thereaction mixture was added 1 N HCl and EtOAc. The aqueous layer (the pH˜1) was extracted with EtOAc (3×), washed with saturated NaHCO₃, driedover Na₂SO₄, and concentrated to give a red oil. The crude product waspurified on Biotage system (generally gradient elution 7% EtOAc:93%Hexanes to 60% EtOAc:40% Hexanes) to give the appropriate lactam as anorange foam (typically 74% yield).

General Protocol to Produce Intermediate 18

To a solution of lactam (1 equivalent) in CH₂Cl₂ (typically ˜0.1 M insubstrate concentration) at room temperature was added PCl₅ (1.6equivalent). The homogeneous reaction mixture was allowed to stir for1.5 h, at which point LC-MS analysis indicated complete consumption ofSM. The reaction was quenched by the addition of 2 M Na₂CO₃ and theaqueous layer was extracted with EtOAc (3×). The combined organicextracts were washed with water, dried over Na₂SO₄, and concentrated togive a brown oil. The crude chloro-imine was purified on Biotage systemusing gradient elution (generally 5% EtOAc:95% Hexanes to 20% EtOAc:80%Hexanes) to give the titled compound as an white foam (typically 50-70%yield).

Chloro-Imine Couplings to Produce Intermediate 19

a. Suzuki Reactions on Chloro-Imines (Step H).

To a solution of chloro-imine

18 (1 equivalent) in toluene (˜0.2 M in substrate) was added the desiredboronic acid or boronic ester (1.2-2 equivalent) and Pd(PPh₃)₄ (˜5 mol%). The reaction was evacuated and purged with N₂ (g) (3×), followed byaddition of aqueous solution of Na₂CO₃ (2 equivalent). The heterogeneousreaction mixture was heated to 82° C. for 0.5-1 h. After completeconsumption of chloro-imine as detected by LC-MS or TLC, the reactionmixture was cooled to ambient temperatures. The organic layer wasremoved and the aqueous layer was extracted with EtOAc (3×), thecombined organic extracts were washed with water, brine, andconcentrated in vacuo. The crude couple product was purified on Biotagesystem.

b. Stille Reactions on Chloro-Imines (Step I).

To a solution of chloro-imine 18 (1 equivalent) in toluene (˜0.1 M insubstrate) was added the desired tributyl aryl stannane (1.7-2equivalent) and Pd(PPh₃)₄ (˜5 mol %). The reaction was evacuated andpurged with N₂ (g) (3×) and heated to 82° C. for 40 h. After cooling toroom temperature, the organic layer was removed and the aqueous layerwas extracted with EtOAc (3×), the combined organic extracts were washedwith water, brine, and concentrated in vacuo. The crude coupled productwas purified on a Biotage system.

c. Negishi Reactions on Chloro-Imines (Step J).

To a solution of chloro-imine 18 (1 equivalent) in toluene (˜0.1 M insubstrate) was added the desired dialkyl zinc reagent (1.5 equivalent)and PdCl₂(dppf)-CH₂Cl₂ adduct (˜5 mol %). The reaction was evacuated andpurged with N₂ (g) (3×) and heated to 50° C. for 1 h. After cooling toroom temperature, the organic layer was removed and the aqueous layerwas extracted with EtOAc (3×), the combined organic extracts were washedwith water, brine, and concentrated in vacuo. The crude coupled productwas purified on a Biotage system.

d. Nucleophilic Additions on Chloro-Imines (Step K).

Chloro-imine (1 equivalent) was dissolved in neat amine in a microwavevial and heated by 300 W microwave at 160° C. for 2 h. Excess amine wasevaporated under reduced pressure and the crude mixture purified on aBiotage system.

General Procedure for Production of a Compound of Formula I (Step L

To a solution of imino tert-butyl ester 19 (1 equivalent) in CHCl₃(typically 0.5-0.1 M in substrate) was added TFA (40-60 equivalent). Thereaction mixture was heated to 36° C. until LC-MS analysis indicatedcomplete consumption of ester and formation of desired acid. The yellowreaction mixture is cooled to ambient temperatures, concentrated invacuo, and excess TFA is azeotropically removed using toluene (2×),followed by CHCl₃ (2×). The crude carboxylic acid is dried and usedwithout further purification.

To a cooled (0° C.) solution of crude carboxylic acid (1 equivalent) inDMF (typically 0.5-0.1 M in substrate concentration) was sequentiallyadded base (10 equivalent), desired amine 20 (8 equivalent), andcoupling reagent (typically HATU or COMU, 1.5 equivalent). Aftercomplete addition of reagents the reaction mixture was warmed to roomtemperature and allowed to stir until complete consumption of carboxylicacid was detected by LC-MS. The reaction mixture was diluted with EtOAcand water. The organic layer was removed and the aqueous layer wasextracted with EtOAc (3×), the combined organic extracts were washedwith water, brine, and concentrated in vacuo. The crude couple productwas purified on Biotage system.

2-((6S)-4-benzyl-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide(Compound 127).

Compound 127 was also synthesized according to Scheme 1, above, usingbenzylzinc(II) bromide in a Negishi reaction (Step J) to convert thechloroimine 18 to the corresponding benzylimine intermediate and then tothe title product using Step L.

The compounds in Table 5 were made using the general protocol describedabove.

TABLE 5 General Protocol for Compound final two steps No. Physical Data(Scheme 1)* 100 LRMS m/z 356 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L13.08-12.94 (m, 1H), 7.71-7.53 (m, 2H), 7.49-7.31 (m, 1H), 7.02-6.86 (m,1H), 4.09 (s, 1H), 3.24-2.99 (m, 2H), 2.46-2.34 (m, 6H), 1.87 (s, 3H)101 LRMS m/z 370 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.69-7.64(m, 1H), 7.63-7.57 (m, 1H), 7.40-7.34 (m, 1H), 7.00-6.90 (m, 1H),4.12-4.02 (m, 1H), 3.78 (s, 3H), 3.2- 3.01 (m, 2H), 2.43 (s, 3H), 2.41(s, 3H), 1.91 (d, J = 0.69 Hz, 3H) 102 LRMS m/z 382 [M + H]⁺; ¹H NMR(400 MHz, Acetone-d₆) δ H, L 7.88 (s, 1H), 7.45 (dd, J = 2.2, 8.6 Hz,1H), 7.22-7.06 (m, 1H), 6.50 (d, J = 8.5 Hz, 1H), 6.41-6. 29 (m, 1H),5.81 (br. s, 2H), 4.25 (t, J = 7.2 Hz, 1H), 3.27 (d, J = 7.0 Hz, 2H),2.49 (s, 6H), 1.81 (s, 3H) 103 LRMS m/z 401[M + H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ I, L 8.52 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.81(d, J = 8.47 Hz, 1H), 7.72-7.60 (m, 1H), 7.09-6.93 (m, 1H), 4.35- 4.17(m, 1H), 3.26-3.11 (m, 2H), 2.44 (s, 3H), 2.38 (s, 3H), 1.54 (s, 3H) 104LRMS m/z 368 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 9.27 (s, 1H),9.16-9.08 (m, 1H), 7.76-7.60 (m, 1H), 7.46- 7.36 (m, 1H), 7.13-6.98 (m,1H), 4.37-4.19 (m, 1H), 3.29- 3.13 (m, 2H), 2.45 (s, 3H), 2.43 (s, 3H),1.63 (s, 3H) 105 LRMS m/z 368 [M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δH, L 9.16 (s, 1H), 8.69 (s, 2H), 7.17 (br. s, 1H), 6.41 (br. s, 1H),4.40 (br. s, 1H), 3.37 (d, J = 5.9 Hz, 2H), 2.48 (s, 6H), 1.75 (d, J =0.88 Hz, 3H) 106 LRMS m/z 367 [M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δH, L 8.60 (dd, J = 1.76, 4.7 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 7.70(td, J = 1.9, 7.9 Hz, 1H), 7.36 (ddd, J = 0.73, 4.9, 7.8 Hz, 1H), 7.16(br. s, 1H), 6.39 (br. s, 1H), 4.37 (br. s, 1H), 3.35 (d, J = 7.0 Hz,2H), 2.48 (s, 3H), 2.46 (d, J = 0.59 Hz, 3H), 1.69 (s, 3H) 107 LRMS m/z367 [M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L 8.62-8.54 (m, 2H),7.31-7.25 (m, 2H), 7.16 (br. s, 1H), 6.40 (br. s, 1H), 4.40 (br. s, 1H),3.35 (d, J = 6.1 Hz, 2H), 2.47 (s, 3H), 2.45 (d, J = 0.88 Hz, 3H), 1.70(d, J = 0.88 Hz, 3H) 108 LRMS m/z 366 [M + H]⁺; ¹H NMR (400 MHz,Acetone-d₆) δ H, L 7.54-7.24 (m, 5H), 7.20-7.06 (m, 1H), 6.46-6.25 (m,1H), 4.33 (br. s, 1H), 3.31 (d, J = 6.7 Hz, 2H), 2.46 (s, 3H), 2.43 (d,J = 0.59 Hz, 3H), 1.65 (d, J = 0.59 Hz, 3H) 109 LRMS m/z 384 [M + H]⁺;¹H NMR (400 MHz, CDCl₃) δ 7.40 H, L (dd, J = 5.6, 8.8 Hz, 2H), 7.11 (t,J = 8.9 Hz, 3H), 6.39 (br. s, 1H), 4.32 (t, J = 7.0 Hz, 1H), 3.31 (d, J= 6.7 Hz, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 1.69 (d, J = 0.59 Hz, 3H) 110LRMS m/z 400 [M(+H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L 7.42-7.31 (m,4H), 7.17 (br. s, 1H), 6.44 (br. s, 1H), 4.34 (t, J = 6.9 Hz, 1H), 3.33(d, J = 7.0 Hz, 2H), 2.46 (s, 3H), 2.44 (d, J = 0.59 Hz, 3H), 1.69 (d, J= 0.59 Hz, 3H) 111 LRMS m/z 400 [M + H]⁺=,; ¹H NMR (400 MHz, Acetone-d₆)H, L δ 7.53-7.29 (m, 4H), 7.17 (br. s, 1H), 6.44 (br. s, 1H), 4.50 (br.s, 1H), 3.32 (m, 2H), 2.48 (s, 3H), 2.36 (s, 3H), 1.55 (s, 3H) 112 LRMSm/z 414 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ H, L 7.61 (br, 1H), 7.36(d, J = 9 Hz, 1H), 7.21 (d, J = 9 Hz, 1H), 7.02 (s, 1H), 6.80 (br, 1H),4.28-4.26 (m, 1H), 3.17-3.10 (m, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 2.15(s, 3H), 1.42 (s, 3H) 113 LRMS m/z 419 [M + H]⁺; ¹H NMR (400 MHz,Acetone-d₆) δ H, L 7.78 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H),7.49-7.40 (m, 1H), 4.44-4.36 (m, 1H), 3.33-3.24 (m, 4H), 2.47 (s, 3H),2.45 (s, 3H), 1.67 (s, 3H), 1.14 (t, J = 7.17 Hz, 3H) 114 LRMS m/z 437[M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L 7.77 (d, J = 8.5 Hz, 2H),7.75-7.70 (m, 1H), 7.54 (d, J = 8.5 Hz, 2H), 4.59 (t, J = 4.5 Hz, 1H),4.47 (t, J = 5.0 Hz, 1H), 4.41 (br. s, 1H), 3.70-3. 46 (m, 2H),3.29-3.40 (m, 2H), 2.47 (s, 3H), 2.45 (s 3H), 1.67 (s, 3H) 115 LRMS m/z391 [M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L 7.78 (d, J = 8.8 Hz,2H), 7.54 (d, J = 8.8 Hz, 2H), 7.16 (br. s, 1H), 6.40 (br. s, 1H), 4.38(br. s, 1H), 3.35 (d, J = 6.7 Hz, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 1.68(s, 3H) 116 LRMS m/z 409 [M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L7.90 (d, J = 8.8 Hz, 2H), 7.49-7.45 (m, 1H), 7.43 (d, J = 8.8 Hz, 2H),7.15 (br. s, 1H), 6.65 (br. s, 1H), 6.38 (br. s, 1H), 4.36 (br. s, 1H),3.34 (br. s, 2H), 2.47 (s, 3H), 2.44 (s, 3H), 1.66 (s, 3H) 117 LRMS m/z409 [M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L 8.00-7.87 (m, 2H),7.52-7.33 (m, 3H), 7.16 (br. s, 1H), 6.64 (br. s, 1H), 6.38 (br. s, 1H),4.36 (t, J = 6.4 Hz, 1H), 3.33 (d, J = 7.0 Hz, 2H), 2.47 (s, 3H), 2.43(s, 3H), 1.65 (s, 3H) 118 LRMS m/z 423 [M + H]⁺; ¹H NMR (400 MHz,Acetone-d₆) δ H, L 9.39-9.30 (m, 1H), 7.63 (m, 2H), 7.29 (m, 2H), 7.16(br. s, 1H), 6.38 (br. s, 1H), 4.35-4.18 (m, 1H), 3.30 (m, 2H), 2.45 (s,3H), 2.44 (s, 3H), 2.07 (s, 3H), 1.65 (s, 3H) 119 LRMS m/z 397 [M + H]⁺;¹H NMR (400 MHz, Acetone-d₆) δ H, L 7.57 (d, J = 7.0 Hz, 1H), 7.14 (br.s, 1H), 6.38 (br. s, 1H), 6.25 (dd, J = 1.8, 7.0 Hz, 1H), 6.12 (d, J =1.8 Hz, 1H), 4.34 (br. s, 1H), 3.46 (s, 3H), 3.32 (d, J = 6.4 Hz, 2H),2.47 (s, 3H), 2.46 (d, J = 0.59 Hz, 3H), 1.91 (s, 3H) 120 LRMS m/z 397[M + H]⁺; ¹H NMR (400 MHz, Acetone-d₆) δ H, L 7.56 (d, J = 2.3 Hz, 1H),7.49 (dd, J = 2.6, 9.4 Hz, 1H), 7.25- 7.12 (m, 1H), 6.48-6. 36 (m, 1H),6.36-6.30 (m, 1H), 4.25 (t, J = 7.0 Hz, 1H), 3.48-3.43 (m, 3H), 3.28(dd, J = 2.3, 7.0 Hz, 2H), 2.47-2.41 (m, 6H), 1.97-1.93 (m, 3H) 121 LRMSm/z 388 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.00 K, L (br. s, 1H), 5.43(br. s, 1H), 4.10-4.03 (m, 1H), 3.69-3.53 (m, 2H), 3.17-2.92 (m, 6H),2.79-2. 53 (m, 2H), 2.45 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H), 2.26 (s,3H) 122 LRMS m/z 375 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.08- K, L 6.71(m, 1H), 5.47 (br. s, 1H), 4.30-4.15 (m, 1H), 3.88 (br. s, 2H), 3.63 (m,4H), 3.11 (m, 4H), 2.46 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H) 123 LRMS m/z402 [M + H]⁺ K, L 124 LRMS m/z 332 [M + H]⁺; ¹H NMR (400 MHz,Acetone-d₆) δ J, L 7.07 (br. s, 1H), 6.30(br. s, 1H), 4.20-4.10 (m, 1H),3.27- 3.04 (m, 2H), 2.65-2.48 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H), 2.24(s, 3H), 1.44-1.20 (m, 2H), 0.72-0.52 (m, 3H) 125 LRMS m/z 330 [M + H]⁺;¹H NMR (400 MHz, Acetone-d₆) δ J, L 7.01 (br. s, 1H), 6.28 (br. s, 1H),4.20-4.01 (m, 1H), 2.94- 3.23 (m, 2H), 2.45 (s, 3H), 2.42-2.38 (m, 6H),1.79 (m, 1H), 1.12-1.04 (m, 1H), 1.02-0.93 (m, 1H), 0.87 (br. s, 1H),0.67 (d, J = 7.3 Hz, 1H) 126 LRMS m/z 372 [M + H]⁺; ¹H NMR (300 MHz,CDCl₃) δ 4.04 J, L (t, J = 7.2 Hz, 1H), 3.31-3.21 (m, 2H), 2.69-2.59 (m,1H), 2.44 (s, 6H), 2.28 (s, 3H), 2.03-1.99 (m, 1H), 1.83-1.79 (m, 1H),1.69-1.55 (m, 3H), 1.39-1.31 (m, 1H), 1.20-1.14 (m, 4H) 127 LRMS m/z 380[M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.17- J, L 7.10 (m, 3H), 6.90-6.87(m, 2H), 6.52 (br, 1H), 5.52 (br, 1H), 4.12 (t, J = 6.0 Hz, 1H),4.04-3.86 (m, 2H), 3.27-3.09 (m, 2H), 2.39-2.32 (m, 9H) 128 LRMS m/z 380[M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.73-7.55 (m, 3H), 7.40 (d, J= 8.70 Hz, 2H), 7.24-7.12 (m, 3H), 7.06-6.94 (m, 1H), 4.32-4.20 (m, 1H),3.20 (s, 2H), 2.52 (s, 3H), 1.91 (s, 3H) 129 LRMS m/z 364 [M + H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ H, L 7.72-7.64 (m, 2H), 7.63-7.57 (m, 1H),7.32-7.27 (m, 1H), 7.25-7.20 (m, 2H), 7.19-7.11 (m, 2H), 7.01 (br. s,1H), 4.25 (t, J = 7.32 Hz, 1H), 3.18 (dd, J = 1.60, 7.32 Hz, 2H), 2.50(s, 3H), 1.91 (s, 3H) 130 LRMS m/z 371 [M + H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ H, L 7.81 (d, J = 8.70 Hz, 2H), 7.73-7.57 (m, 3H), 7.38-7.26(m, 3H), 7.02 (br. s, 1H), 4.31 (t, J = 7.32 Hz, 1H), 3.26-3.13 (m, 2H),2.51 (s, 3H), 1.88 (s, 3H) 131 LRMS m/z 347 [M + H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ H, L 8.55 (d, J = 6.14 Hz, 2H), 7.70-7.61 (m, 3H), 7.32 (s,1H), 7.12 (d, J = 6.14 Hz, 2H), 7.02 (bs, 1H), 4.32 (t, J = 7.31 Hz,1H), 3.25-3.08 (m, 2H), 2.51 (s. 3H), 1.91 (s, 3H) 132 LRMS m/z 414 [M +H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.74-7.60 (m, 5H), 7.38 (d, J =8.24 Hz, 2H), 7.31 (d, J = 7.10 Hz, 1H), 7.03 (br. s, 1H), 4.32 (t, J =7.32 Hz, 1H), 3.22 (dd, J = 1.49, 7.44 Hz, 2H), 2.52 (s, 3H), 1.89 (s,3H) 133 LRMS m/z 381 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ I, L 8.44(dd, J = 0.69, 2.52 Hz, 1H), 8.02 (dd, J = 2.52, 8.47 Hz, 1H), 7.90 (dd,J = 0.80, 8.58 Hz, 1H), 7.67 (br. s, 1H), 7.62 (d, J = 7.55 Hz, 1H),7.56 (d, J = 7.32 Hz, 1H), 7.25 (s, 1H), 7.03 (br. s, 1H), 4.33 (t, J =7.32 Hz, 1H), 3.24-3.15 (m, 2H), 2.50 (s, 3H) 1.98-1.67 (m, 3H) 134 LRMSm/z 389 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.97 (br. s, 1H),7.80 (d, J = 8.47 Hz, 2H), 7.69 (s, 2H), 7.62 (d, J = 7.78 Hz, 1H), 7.41(s, 1H), 7.30 (s, 1H), 7.23 (s, 2H), 7.02 (br. s, 1H), 4.28 (t, J = 7.44Hz, 1H), 3.24-3.15 (m, 2H), 2.52 (s, 3H), 1.89 (s, 3H) 135 LRMS m/z 376[M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.65 (d, J = 6.64 Hz, 2H),7.61-7.54 (m, 1H), 7.28 (d, J = 7.32 Hz, 1H), 7.12 (d, J = 8.24 Hz, 2H),6.99 (br. s, 1H), 6.86 (d, J = 9.16 Hz, 2H), 4.21 (t, J = 7.32 Hz, 1H),3.73 (s, 3H), 3.24-3.02 (m, 2H), 2.50 (s, 3H), 1.90 (s, 3H) 136 LRMS m/z430 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.72-7.65 (m, 3H),7.64-7.57 (m, 1H), 7.36-7.25 (m, 4H), 7.01 (br. s, 1H), 4.28 (t, J =7.44 Hz, 1H), 3.23-3.12 (m, 2H), 2.50 (s, 3H), 1.91 (s, 3H) 137 LRMS m/z367 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 8.55 (d, J = 6.18 Hz,2H), 7.93-7.85 (m, 1H), 7.79-7.74 (m, 1H), 7.71-7.67 (m, 1H), 7.62-7.58(m, 1H), 7.16-7.12 (m, 2H), 7.08-7.03 (m, 1H), 4.46-4.27 (m, 1H),3.26-3.08 (m, 2H), 2.53 (s, 3H) 138 LRMS m/z 384 [M + H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ H, L 7.90-7.82 (m, 1H), 7.73 (s, 1H), 7.69-7.64 (m, 1H),7.61- 7.52 (m, 1H), 7.29-7.20 (m, 2H), 7.15 (s, 2H), 7.05-7.01 (m, 1H),4.33-4.27 (m, 1H), 3.20 (d, J = 7.55 Hz, 2H), 2.53 (s, 3H) 139 LRMS m/z400 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.90-7.83 (m, 1H),7.78-7.69 (m, 1H), 7.70-7.65 (m, 1H), 7.61-7.54 (m, 1H), 7.38 (s, 2H),7.25-7.16 (m, 2H), 7.06- 6.97 (m, 1H), 4.36-4.25 (m, 1H), 3.25-3.14 (m,2H), 2.53 (s, 3H) 140 LRMS m/z 391 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δH, L 7.88 (dd, J = 1.14, 8.01 Hz, 1H), 7.81 (d, J = 8.70 Hz, 2H), 7.76(t, J = 7.90 Hz, 1H), 7.69 (br. s, 1H), 7.59 (dd, J = 1.14, 8.01 Hz,1H), 7.36 (d, J = 8.24 Hz, 2H), 7.05 (br. s, 1H), 4.37 (t, J = 7.32 Hz,1H), 3.23 (dd, J = 3.32, 7.21 Hz, 2H), 2.53 (s, 3H) 141 LRMS m/z 400[M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L 7.90-7.82 (m, 1H), 7.78 (dd,J = 2.29, 8.47 Hz, 1H), 7.64 (br. s, 1H), 7.49-7.44 (m, 2H), 7.41 (d, J= 2.06 Hz, 1H), 7.36- 7.29 (m, 2H), 7.04 (br. s, 1H), 4.48-4.17 (m, 1H),3.15 (br. s, 2H), 2.55 (s, 3H) 142 LRMS m/z 391 [M + H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ H, L 7.94 (s, 1H), 7.87 (d, J = 8.01 Hz, 2H), 7.82-7.74(m, 1H), 7.65 (br. s, 1H), 7.49 (d, J = 8.47 Hz, 2H), 7.40 (d, J = 2.06Hz, 1H), 7.05 (br. s, 1H), 4.40 (br. s, 1H), 3.17 (br. s, 2H), 2.50 (s,3H) 143 LRMS m/z 419 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ H, L8.26-8.14 (m, 1H), 7.87 (d, J = 8.01 Hz, 3H), 7.82-7.76 (m, 1H), 7.48(s, 2H), 7.42-7.37 (m, 1H), 4.65-4.21 (m, 1H), 3.24-2.92 (m, 4H), 2.50(s, 3H), 1.06 (s, 3H) 144 LRMS m/z 366 [M + H]⁺; ¹H NMR (400 MHz,Acetone-d₆) δ H, L 7.87-7.80 (m, 1H), 7.71 (ddd, J = 1.90, 6.58, 8.19Hz, 1H), 7.51-7.34 (m, 6H), 7.13 (br. s, 1H), 6.38 (br. s, 1H), 4.48(br. s, 1H), 3.40-3.19 (m, 2H), 2.53 (s, 3H) 145 LRMS m/z 424 [M + H]⁺;¹H NMR (400 MHz, Acetone-d₆) δ H, L 7.86-7.80 (m, 1H), 7.75-7.67 (m,1H), 7.49 (br. s, 1H), 7.46-7.35 (m, 6H), 4.48 (br. s, 1H), 3.50-3.35(m, 4H), 3.33- 3.30 (m, 3H), 3.30-3.22 (m, 2H), 2.53 (s, 3H) 146 LRMSm/z 362 [M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.59- H, L 7.58 (m, 2H),7.46-7.43 (m, 4H), 6.84-6.81 (m, 2H), 6.43-6.42 (br, 1H), 5.59-5.58 (br,1H), 4.41 (t, J = 2.1 Hz, 1H), 3.80 (s, 3H), 3.35-3.26 (m, 2H), 2.55 (s,3H) 147 LRMS m/z 362 [M + H]⁺; ¹H NMR (300 MHz, Acetone-d₆) δ H, L 7.87(d, J = 0.6, 1H), 7.84-7.71 (m, 1H), 7.51-7.42 (m, 2H), 7.31-7.20 (m,2H), 7.17-7.01 (m, 2H), 6.91 ( d, J = 7.5, 1H), 6.47 (s, 1H), 4.52 (s,1H), 3.80 (d, J = 5.1, 3H), 3.33 (t, J = 6.9, 2H), 2.59 (s, 3H) 148 LRMSm/z 357 [M + H]⁺; ¹H NMR (300 MHz, Acetone-d₆) δ H, L 7.92-7.88 (m, 1H),7.83-7.78 (m, 3H), 7.64-7.61 (m, 2H), 7.51-7.49 (m, 2H), 7.19 (s, 1H),6.45 (s, 1H), 4.57 (d, J = 7.2, 1H), 3.38-3.34 (m, 2H), 2.58 (s, 3H) 149LRMS m/z 385 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ H, L 7.62-7.59 (m,4H), 7.50-7.47 (m, 2H), 7.30 (m, 2H), 6.08 (br, 1H), 4.58 (t, J = 6.9Hz, 1H), 3.42-3.36 (m, 2H), 3.28-3.26 (m, 2H), 2.60 (s, 3H), 1.22 (t, J= 7.2 Hz, 3H) 150 LRMS m/z 415 [M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.62-H, L 7.59 (m, 4H), 7.53-7.50 (m, 2H), 7.31-7.28 (m, 2H), 6.50-6.49 (br,1H), 4.55 (t, J = 1.8 Hz, 1H), 3.53 (br, 4H), 3.4 (s, 3H), 3.30-3.27 (s,2H), 2.55 (s, 3H) 151 LRMS m/z 380 [M + H]⁺; ¹H NMR (300 MHz,Acetone-d₆) δ H, L 7.86 (d, J = 7.5, 1H), 7.73-7.68 (m, 1H), 7.43-7.37(m, 1H), 7.30-7.23 (m, 3H), 7.12 (d, J = 7.5, 2H), 6.43-6.41 (m, 1H),4.6 (m, 1H), 3.32-3.27 (m, 2H), 2.59 (s, 3H), 1.98 (s, 3H) 152 LRMS m/z341 [M + H]⁺; ¹H NMR (300 MHz, Acetone-d₆) δ K, L 7.92 (d, J = 7.5, 1H),7.77-7.70 (m, 2H), 7.50 (d, J = 7.5, 1H), 7.1 (s, 1H)), 6.26 (s, 1H),4.31 (s, 1H), 3.76-3.58 (m, 4H), 3.12-2.88 (m, 6H), 2.52 (s, 3H) *Allcompounds were prepared using general procedures A-G, and the final twosteps were as indicated in the table. Either version of generalprocedure A could be used.

Example 15 Synthesis of Compounds of Formula III, wherein R^(C) is4-Chlorophenyl, R₂ is Hydrogen and R₃ is OH or N(R′)(R″)

Certain compounds of Formula III may be synthesized according to Scheme2, below.

Specific examples of intermediates and compounds made and/or used inthis scheme are as follows.(4-(2-formylphenyl)-5-methylisoxazol-3-yl)methyl acetate

To a resealable vial was added palladium(II) chloride (4.49 mg, 0.025mmol), potassium acetate (1.24 g, 12.7 mmol), and 2-bromobenzaldehyde(0.59 mL, 5.07 mmol). The vial was sealed and evacuated/backfilled withN₂ (3×) before addition of 3-(chloromethyl)-5-methylisoxazole (1.00 g,7.60 mmol) as a solution in DMA (25 mL). The vial was then heated to130° C. overnight. The reaction was cooled to room temperature anddiluted with water. The solution was extracted with ether and thecombined organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated. The crude residue was purified via Biotage (EtOAc/hex)to afford (4-(2-formylphenyl)-5-methylisoxazol-3-yl)methyl acetate (1.01g, 3.90 mmol). LC/MS m/z 260 [M+H]⁺.

(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanol

To a round bottomed flask was added(4-(2-formylphenyl)-5-methylisoxazol-3-yl)methyl acetate (1.01 g, 3.90mmol) and THF (20 mL) before the reaction was cooled to −78° C. To thissolution was added 1.0 M (4-chlorophenyl)magnesium bromide (4.68 mL,4.68 mmol) and the reaction stirred at −78° C. for 30 min beforeaddition of ammonium chloride solution. The reaction was warmed to roomtemperature and diluted with EtOAc. The layers were separated and theaqueous was extracted with EtOAc. The combined organics were washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude residuewas taken up in THF:MeOH:Water (2:2:1, 20 mL) before addition of lithiumhydroxide hydrate (0.491 g, 11.70 mmol). The reaction was stirred atroom temperature for 1 h before diluting with water and EtOAc. Thelayers were separated and the aqueous was extracted with EtOAc. Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated. The crude diol was purified via Biotage (EtOAc/hex) toafford(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanol(1.14 g, 3.44 mmol). LC/MS m/z 330 [M+H]⁺.

4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde

To a round bottomed flask was added CH₂Cl₂ and oxalyl chloride (1. 21mL, 13.8 mmol) before the solution was cooled to −78° C. To thissolution was added DMSO (1.47 mL, 20.65 mmol) and the solution stirredfor 15 min before addition of(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanol(1.14 g, 3.44 mmol) dissolved in CH₂Cl₂. The reaction was stirred for 15min at −78° C. before addition of Et₃N (3.84 mL, 27.5 mmol) and warmingthe reaction to room temperature overnight. This reaction was dilutedwith water and the layers separated. The aqueous was extracted withCH₂Cl₂ and the combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage (EtOAc/hex) toafford 4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde(1.10 g, 3.38 mmol). LC/MS m/z 326 [M+H]⁺.

6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-ol

(Compound 153) and6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-amine

(Compound 154).

To a resealable vial was added4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde (0.052 g,0.160 mmol) and ammonia (1.85 mL, 12.93 mmol, 7M in MeOH). The vial wassealed and the reaction stirred at room temperature for two days. Thesolution was concentrated and the crude residue was purified via Biotage(EtOAc/hex) to afford two products. Minor:6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-amine(0.0026 g, 0.008 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.64 (m, 2H),7.49-7.43 (m, 3H), 7.42-7.37 (m, 2H), 7.31 (d, J=7.32 Hz, 1H), 4.88 (s,1H), 2.86-2.71 (m, 2H), 2.65 (s, 3H). LC/MS m/z 324 [M+H]⁺. Major:6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-ol (27mg, 0.083 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.64 (m, 2H),7.51-7.38 (m, 6H), 7.32 (d, J=7.78 Hz, 1H), 6.84 (br. s, 1H), 5.51 (s,1H), 2.65 (s, 3H); LC/MS m/z 325 [M+H]⁺.

Ethyl(6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)carbamate

(Compound 155).

To a microwave vial was added4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde (0.055 g,0.169 mmol) and ammonia (1.95 mL, 7M in MeOH, 13.7 mmol). The vial wassealed and the reaction heated to 120° C. for 20 min. The solution wascooled to room temperature and concentrated. The crude residue waspurified via Biotage to afford6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-aminewhich was taken up in CH₂Cl₂ before addition of pyridine (0.013 mL,0.169 mmol) and ethyl chloroformate (0.016 mL, 0.169 mmol). The reactionwas stirred at room temperature for 1 h before addition of sat. aqueousNaHCO₃. The layers were separated and aqueous extracted with CH₂Cl₂. Thecombined organics were dried over Na₂SO₄, filtered, and concentrated.The crude residue was purified via Biotage (EtOAc/hex) afford ethyl6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-ylcarbamate(0.0057 g, 0.014 mmol). ¹H NMR (500 MHz, Acetone-d₆) δ 7.81-7.76 (m,1H), 7.75-7.70 (m, 1H), 7.53-7.46 (m, 3H), 7.45-7.40 (m, 3H), 7.38 (d,J=9.27 Hz, 1H), 5.85 (d, J=8.79 Hz, 1H), 4.13 (q, J=7.32 Hz, 2H), 2.70(s, 3H), 1.25 (t, J=7.08 Hz, 3H); LC/MS m/z 396 [M+H]⁺.

Example 16 Synthesis of Compounds of Formula I, Wherein R₃ is Methyl

Certain compounds of Formula II or III may be synthesized according toScheme 3, below.

Specific examples of intermediates and compounds made and/or used inthis scheme are as follows.

(2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone

To a resealable vial was added4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde fromExample 15 (0.100 g, 0.307 mmol) and THF (2.0 mL). The vial was sealedand cooled to −78° C. before addition of methylmagnesium chloride (0.107mL, 0.322 mmol). The reaction was stirred at −78° C. for 30 min beforeaddition of ammonium chloride solution and water. The aqueous wasextracted with EtOAc and the combined layers washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford crude(4-chlorophenyl)(2-(3-(1-hydroxyethyl)-5-methylisoxazol-4-yl)phenyl)methanone(0.092 g, 0.269 mmol).

To a round bottomed flask was added(4-chlorophenyl)(2-(3-(1-hydroxyethyl)-5-methylisoxazol-4-yl)phenyl)methanone(0.092 g, 0.269 mmol), CH₂Cl₂ (3.0 mL), and Et₃N (0.075 mL, 0.538 mmol).The vial was cooled to 0° C. before addition of methanesulfonyl chloride(0.025 mL, 0.323 mmol) and the reaction stirred for 45 min at 0° C.before quenching with water. The layers were separated and the aqueousextracted with CH₂Cl₂. The combined organics were dried over Na₂SO₄,filtered, and concentrated. The crude residue was taken up in DMF (2 mL)and sodium azide (0.053 g, 0.808 mmol) was added. The reaction wasstirred at room temperature overnight before being diluted with waterand EtOAc. The layers were separated and the aqueous was extracted withEtOAc. The combined organics were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified via Biotage(EtOAc/hex) to afford(2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone(0.073 g, 0.199 mmol). LC/MS m/z 389 [M+Na]⁺.

6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[c]isoxazolo[4,3-e]azepine(Compound 156).

To a round bottomed flask was added(2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone(0.073 g, 0.199 mmol), toluene, and trimethylphosphine (0.239 mL, 1M intoluene, 0.239 mmol). The reaction was stirred at room temperatureovernight before concentrating. The crude residue was purified viaBiotage (EtOAc/hex) to afford impure6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[c]isoxazolo[4,3-e]azepine. Thismaterial was purified via preparatory HPLC and the fractions neutralizedbefore being extracted with EtOAc. The organics were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude residue waspurified via Biotage (EtOAc/hex) to afford6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[c]isoxazolo[4,3-e]azepine(0.0011 g, 0.003 mmol). ¹H NMR (400 MHz, Acetone-d₆) δ 7.74-7.70 (m,1H), 7.69-7.63 (m, 1H), 7.49-7.41 (m, 3H), 7.41-7.33 (m, 3H), 4.24-4.16(m, 1H), 2.66 (s, 3H), 1.86 (d, J=6.35 Hz, 3H); LC/MS m/z 323 [M+H]⁺.

Example 17 Synthesis of Compounds of Formula I, Wherein R₂ is Hydrogenand R₃ is (S)—CH₂—C(O)—N(R′)(R″)

Certain compounds of Formula II or III may be synthesized according toScheme 4, below.

Specific examples of intermediates and compounds made and/or used inthis scheme are as follows.

(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone

To a round bottomed flask was added(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoatefrom Example 12 (0.780 g, 1.806 mmol), THF (4 mL), MeOH (4 mL), andwater (2 mL). The solution was cooled to 0° C. before addition oflithium hydroxide monohydrate (0.227 g, 5.42 mmol). The reaction wasstirred at 0° C. for 45 min before diluting with water and extractingwith EtOAc. The combined organics were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude residue was purified viaBiotage (EtOAc/hex) to afford(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone(0.451 g, 1.376 mmol). LC/MS m/z 328 [M+H]⁺.

4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde

To a round bottomed flask was added CH₂Cl₂ (15 mL) and oxalyl chloride(0.24 mL, 2.75 mmol). The solution was cooled to −78° C. before additionof DMSO (0.29 mL, 4.13 mmol) and the reaction stirred at −78° C. for 15minutes before addition of(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone(0.451 mg, 1.38 mmol) dissolved in CH₂Cl₂ (5 mL). The reaction wasstirred an additional 15 min at −78° C. before addition of Et₃N (0.959mL, 6.88 mmol) and removal of the cold bath. After warming to roomtemperature water was added and the layers separated. The aqueous wasextracted with CH₂Cl₂ and the combined organics were dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified via Biotage(EtOAc/hex) to afford4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde (0.448 g,1.38 mmol). LC/MS m/z 326 [M+H]⁺.

(R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide

To a round bottomed flask was added4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde (0.224 g,0.688 mmol) and THF (3 mL). To this solution were addedtetraethoxytitanium (0.29 mL, 1.38 mmol) and(R)-2-methylpropane-2-sulfinamide (0.092 g, 0.756 mmol) and the reactionstirred at room temperature overnight. The reaction was diluted withbrine (3 mL) and EtOAc and this mixture was stirred vigorously for 1.5h. This solution was filtered though Celite and the layers separated.The aqueous was extracted with EtOAc and the combined organics weredried over Na₂SO₄, filtered, and concentrated. The crude residue waspurified via Biotage (EtOAc/hex) to afford(R,E)-N4(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide(0.233 g, 0.543 mmol). LC/MS m/z 429 [M+H]⁺.

(3S)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate

and(3R)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate

To a round bottomed flask was added(R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide(0.083 g, 0.194 mmol) in THF (0.5 mL). This solution was cooled to 0° C.before addition of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.464mL, 0.232 mmol) and stirring at 0° C. for 1 h before addition of anothermore zinc reagent (0.388 mL, 0.194 mmol). After stiffing 3 h at 0° C.the solution was quenched with aqueous ammonium chloride solution andEtOAc added. The layers were separated and the aqueous extracted withEtOAc. The combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude residue was purified via Biotage(EtOAc/hex) to afford (3S)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(R_(f)(1:1 EtOAc:hex)=˜0.3, Mass: 0.043 g, LC/MS m/z 545 [M+H]⁺) and(3R)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(R_(f)(1:1 EtOAc:hex)=˜0.15, Mass: 0.045 g, LC/MS m/z 545 [M+H]⁺).

2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(Compound 157).

To a resealable vial was added (3S)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.043 g, 0.079 mmol), EtOH (3 mL), and acetyl chloride (0.017 mL, 0.237mmol). The vial was sealed and heated to 60° C. for 1.75 h before beingcooled to room temperature and diluting with saturated NaHCO₃ and EtOAc.The layers were separated and the aqueous was extracted with EtOAc. Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated. The crude residue was purified via Biotage (EtOAc/hex)to afford tert-butyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.026 g, 0.061 mmol). ¹H NMR (400 MHz, Acetone-d₆) δ 7.87-7.83 (m, 1H),7.76-7.70 (m, 1H), 7.51-7.41 (m, 2H), 7.40 (s, 4H), 4.40 (br. s, 1H),3.32 (d, J=7.19 Hz, 2H), 2.54 (s, 3H), 1.48 (s, 9H); LC/MS m/z 423[M+H]⁺.

Tert-butyl2-((4R)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate

(Compound 158).

The title compound was made in a similar manner as above starting from(3R)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate.¹H NMR (400 MHz, Acetone-d₆) δ 7.85 (dd, J=0.83, 7.66 Hz, 1H), 7.76-7.70(m, 1H), 7.50-7.41 (m, 2H), 7.40 (s, 4H), 4.40 (br. s, 1H), 3.32 (d,J=7.4 Hz, 2H), 2.54 (s, 3H), 1.48 (s, 9H); LC/MS m/z 423 [M+H]⁺.

2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-N-ethylacetamide

(Compound 159).

To a round bottomed flask was added tert-butyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.019 g, 0.046 mmol), CH₂Cl₂ (2 mL), and TFA (0.400 mL, 5.19 mmol). Thereaction was stirred for 1 h before being concentrated. The cruderesidue was dissolved in DMF (1 mL) and ethylamine (0.032 mL, 0.064mmol), HATU (0.026 g, 0.068 mmol), and Hunig's base (0.024 mL, 0.137mmol) were added. The reaction was stirred at room temperature for 1 hbefore diluting with water and methanol and purification via preparatoryHPLC. The fractions were neutralized and the aqueous extracted withCH₂Cl₂. The combined organics were dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage (EtOAc/hex) toafford2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-N-ethylacetamide(0.0068 g, 0.017 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27-8.13 (m, 1H),7.83 (d, J=7.3 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.49-7.36 (m, 4H),7.34-7.25 (m, 2H), 4.42-4.23 (m, 1H), 3.14 (dd, J=6.98, 12.7 Hz, 4H),2.51 (s, 3H), 1.07 (t, J=7.2 Hz, 3H); LC/MS m/z 394 [M+H]⁺.

2-bromo-N,5-dimethoxy-N-methylbenzamide

was prepared according to the procedure described in Tetrahedron, 2001,57, 7765-7770.(2-bromo-5-methoxyphenyl)(4-chlorophenyl)methanone

and (4-chlorophenyl)(3-methoxyphenyl)methanone

To a round bottomed flask was added2-bromo-N,5-dimethoxy-N-methylbenzamide (6.23 g, 22.73 mmol) and THF (75mL). To this solution was added (4-chlorophenyl)magnesium bromide (42mL, 42.0 mmol) and the reaction stirred at room temperature overnight.The solution was diluted with water and EtOAc. The layers were separatedand the aqueous was extracted with EtOAc. The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude residue was purified via Biotage (EtOAc/hex) to afford a mixtureof (2-bromo-5-methoxyphenyl)(4-chlorophenyl)methanone and(4-chlorophenyl)(3-methoxyphenyl)methanone. LC/MS m/z 325 [M+H]⁺.

2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-N-ethylacetamide

(Compound 160).

The title compound was made in a similar manner to2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-N-ethylacetamide,starting from(4-(2-(4-chlorobenzoyl)-4-methylphenyl)-3-methylisoxazol-5-yl)methylbenzoate, which is synthesized according to Example 5. ¹H NMR (400 MHz,Acetone-d₆) δ 7.76 (d, J=8.78 Hz, 1H), 7.46-7.41 (m, 2H), 7.41-7.36 (m,2H), 7.31 (dd, J=2.6, 8.8 Hz, 1H), 6.96 (d, J=2.6 Hz, 1H), 4.53-4.43 (m,1H), 3.82-3.76 (m, 3H), 3.36-3.13 (m, 4H), 2.50 (s, 3H), 1.14 (t, J=7.31Hz, 3H); LC/MS m/z 424 [M+H]⁺.

(R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

This material can be made in a similar manner as(R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamidestarting from4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde (1.10 g,3.38 mmol). LC/MS m/z 429 [M+H]⁺.

(3S)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1dimethylethylsulfinamido)propanoate

To a round bottomed flask was added(R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide(0.480 g, 1.12 mmol) and THF (6 mL). This solution was cooled to 0° C.before addition of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (4.48 mL,2.24 mmol). The solution was stirred at 0° C. before for 3.5 h beforeaddition of more of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (1.12mL, 0.560 mmol). The reaction was stirred for an additional 2.5 h beforebeing diluted with aqueous NH₄Cl and EtOAc. The layers were separatedand the aqueous was extracted with EtOAc. The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude residue was purified via Biotage (EtOAc/hex) to afford(3S)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.118 g, 0.216 mmol) and (3R)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.094 g, 0.172 mmol). LC/MS m/z 545 [M+H]⁺.

Tert-butyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)acetate

(Compound 161) and Ethyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)acetate

(Compound 162).

To a resealable vial was added (3S)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.118 g, 0.216 mmol), EtOH, and acetyl chloride (0.046 mL, 0.647 mmol).The vial was sealed and heated to 60° C. for 2 h. The reaction wascooled to room temperature and diluted with a solution of NaHCO₃ andEtOAc. The layers were separated and the aqueous was extracted withEtOAc (3×). The combined organics were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude residue was purified viaBiotage (EtOAc/hex) to afford two products. Major: tert-butyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)acetate(0.062 g, 0.147 mmol), 423 [M+H]⁺. Minor: ethyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)acetate(0.0036 g, 0.0091 mmol). ¹H NMR (500 MHz, acetone-d₆) δ 7.78-7.74 (m,1H), 7.70 (dt, J=1.5, 7.6 Hz, 1H), 7.50-7.46 (m, 1H), 7.45-7.42 (m, 2H),7.41-7.36 (m, 3H), 4.57 (t, J=7.08 Hz, 1H), 4.20-4.14 (m, 2H), 3.36 (d,J=7.3 Hz, 2H), 2.68 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); LC/MS m/z 395[M+H]⁺.

2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)-N-ethylacetamide

(Compound 163).

To a round bottomed flask was added tert-butyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)acetate(0.059 g, 0.140 mmol), CH₂Cl₂ (2 mL), and TFA (0.400 mL, 5.19 mmol). Thereaction was stirred at room temperature for 2 h before concentrating.The crude residue was dried for 30 min before addition of DMF (2 mL),ethylamine (0.098 mL, 0.195 mmol, 2M in THF), HATU (0.080 g, 0.209mmol), and Hunig's Base (0.073 mL, 0.419 mmol). The reaction was stirredat room temperature for 1 h before diluting with water and extractingwith EtOAc. The combined organics were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude residue was purified viaBiotage (EtOAc/hex) to afford2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)-N-ethylacetamide(0.022 g, 0.056 mmol). ¹H NMR (500 MHz, Acetone-d₆) δ 7.76-7.72 (m, 1H),7.71-7.66 (m, 1H), 7.49-7.42 (m, 3H), 7.41-7.36 (m, 3H), 7.32 (br. s,1H), 4.62 (dd, J=5.4, 8.3 Hz, 1H), 3.35-3.21 (m, 2H), 3.20-3.09 (m, 2H),2.67 (s, 3H), 1.14 (t, J=7.3 Hz, 3H); LC/MS m/z 394.

2-((4R)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)-N-ethylacetamide

(Compound 189).

This material was made in a similar manner as2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepin-4-yl)-N-ethylacetamide,starting from (3R)-tert-butyl3-(4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate.¹H NMR (500 MHz, Acetone-d₆) δ 7.76-7.72 (m, 1H), 7.71-7.66 (m, 1H),7.49-7.42 (m, 3H), 7.41-7.36 (m, 3H), 7.32 (br. s, 1H), 4.62 (dd, J=5.4,8.3 Hz, 1H), 3.35-3.21 (m, 2H), 3.20-3.09 (m, 2H), 2.67 (s, 3H), 1.14(t, J=7.3 Hz, 3H); LC/MS m/z 394.

Example 18 Synthesis of Compounds of Formula I wherein Ar is Thiophene

The compounds of this example were prepared in the manner set forth inScheme 4, above. Exemplary synthesis of compounds of Formula I whereinAr is thiophene, and intermediates useful in such compound are set forthbelow.

Methyl 4,5-dimethylthiophene-3-carboxylate

This intermediate was prepared according to the procedure described inOrganic Process Research & Development, 2002, 6, 357-366.

N-Methoxy-N,4,5-trimethylthiophene-3-carboxamide

To a cooled (−30° C. to −20° C.) slurry of methyl4,5-dimethylthiophene-3-carboxylate (5.44 g, 32.0 mmol) andN,O-dimethylhydroxylamine hydrochloride (4.80 g, 49.2 mmol) in THF (45mL) at was added slowly (over 15 min) a solution of isopropylmagnesiumbromide (3.85 mL, 11.16 mmol, 2.9 M) in 2-methyl-tetrahydrofuran. Aftercomplete addition of the base, the reaction mixture was warmed to 0° C.and partitioned between 1 N HCl (55 mL) and MTBE (50 mL). The aqueousphase was extracted with MTBE (2×) and the combined organic layer waswashed with water (until the pH of the aqueous was ˜5). The organiclayer was dried over Na₂SO₄ and concentrated to give a light yellow oil.The crude product was purified on Biotage system (gradient elution 7%EtOAc:93% Hexanes to 60% EtOAc:40% Hexanes) to give the titled compoundas a yellow oil (5.17 g, 25.9 mmol, 81% yield). LC/MS m/z 200 [M+H]⁺.

(4-Chlorophenyl)(4,5-dimethylthiophen-3-yl)methanone

To a cooled (−40° C.) solution ofN-methoxy-N,4,5-trimethylthiophene-3-carboxamide (1.77 g, 8.88 mmol) inTHF (10 mL) was slowly added (over 10 min) a solution of4-chlorophenylmagnesium bromide (17 mL, 17.00 mmol, 1 M) in diethylether. The reaction mixture was allowed to gradually warm to roomtemperature and age for several hours. To the mixture was added 1 N HCland the aqueous layer was extracted with EtOAc (2×). The combinedorganic layer was washed with saturated NaHCO₃, water, dried overNa₂SO₄, and concentrated to give an oil. The resultant oil was purifiedon Biotage system (gradient elution 1% EtOAc:99% Hexanes to 4% EtOAc:96%Hexanes) to give the titled compound as white solids (2.00 g, 7.96 mmol,90% yield). LC/MS m/z 251 [M+H]⁺.

(2-Bromo-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone

To a solution of (4-chlorophenyl)(4,5-dimethylthiophen-3-yl)methanone(1.99 g, 7.94 mmol) in DMF (15 mL) was added N-bromosuccinimide (1.55 g,8.71 mmol) in one portion. After 2 h, the reaction mixture waspartitioned between water and MTBE. The aqueous layer was extracted withMTBE and the combined organic layer was washed with 1% sodiumthiosulfate, water, dried over Na₂SO₄ and concentrated to give lightyellow solids. The resultant solids was purified on Biotage system(gradient elution 1% EtOAc:99% Hexanes to 4% EtOAc:96% Hexanes) to givethe titled compound as yellow solids (2.40 g, 7.28 mmol, 92% yield).LC/MS m/z 329 [(M (³⁵Cl, ⁷⁹Br)+H]⁺ and m/z 331 [M+H]⁺.

(4-Chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-4,5-dimethylthiophen-3-yl)methanone

To a solution of(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methylacetate (0.865 g, 3.08 mmol) and(2-bromo-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (0.534 g,1.619 mmol) in 1,4-dioxane (7 mL) and water (2 mL) was addedPdCl₂(dppf)-CH₂Cl₂ adduct (0.090 g, 0.110 mmol) and K₂CO₃ (0.560 g, 4.05mmol). The bi-phasic mixture was heated to 95° C. under a constantstream of N₂ (g). After 5 h, the mixture was cooled to 45° C. andaqueous 1 N NaOH (4.0 mL, 4.00 mmol) was introduced. After an additional1 h, LC-MS analysis shows complete conversion of acetate to alcohol. Themixture was cooled to room temperature, 1 N HCl was added to acidify theaqueous layer (pH ˜1) and the aqueous layer extracted MTBE (2×). Thecombined organic layer was washed with saturated NaHCO₃, brine, driedover Na₂SO₄, and concentrated to give a dark brown oil. The oil wasdiluted with MTBE and stirred over activated charcoal for 15 min, thenfiltered over a plug of silica and Celite. The filter cake was washedwith MTBE (2×) and subsequently concentration gave a brown oil. Theresultant oil was purified on Biotage system (gradient elution 5%EtOAc:95% Hexanes to 40% EtOAc:60% Hexanes) to give the titled compoundas a yellow oil (0.463 g, 1.28 mmol, 79% yield). LC/MS m/z 362 [M+H]⁺.

(R,E)-N-((4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide

To a cooled (−78° C.) solution of oxalyl chloride (0.15 mL, 1.714 mmol)in CH₂Cl₂ (1 mL) was slowly added a solution of DMSO (0.17 mL, 2.396mmol) in CH₂Cl₂ (0.30 mL). After 15 min, a solution of(4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-4,5-dimethylthiophen-3-yl)methanone(0.399 g, 1.10 mmol) in CH₂Cl₂ (2 mL) was slowly added. After 30 min,Et₃N (0.40 mL, 2.87 mmol) was added and the mixture was warmed to roomtemperature. After stirring for an additional 15 min, the reactionmixture was diluted with 1 N HCl and the aqueous layer was extractedwith CH₂Cl₂ (2×). The combined organic layer was washed with saturatedNaHCO₃, water, dried over Na₂SO₄, and concentrated to provide thealdehyde as a light brown oil, which was used directly without furtherpurification.

To a solution of unpurified aldehyde in CH₂Cl₂ (22 mL) was sequentiallyadded (R)-2-methylpropane-2-sulfinamide (0.150 g, 1.24 mmol) andtitanium(IV) ethoxide (0.46 mL, 2.19 mmol). After 24 h, water (15 mL)was slowly introduced to the vigorously stirred reaction. Theheterogeneous mixture was filtered over Celite, the filter cake waswashed with CH₂Cl₂. The organic layer was washed with water, dried overNa₂SO₄, and concentrated to give an orange oil. The resultant oil waspurified on Biotage system (gradient elution, 5% EtOAc:95% Hexanes to40% EtOAc:60% Hexanes) to deliver the titled product (0.450 g, 0.972mmol, 88% yield over 2-steps) as a light yellow oil. LC/MS m/z 463[M+H]⁺.

(3R)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate

and(3S)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate

To a cooled (0° C.) solution of (2-tert-butoxy-2-oxoethyl)zinc(II)chloride (0.200 mL, 0.100 mmol) was added a solution of(R,E)-N-((4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-methylene)-2-methylpropane-2-sulfinamide(0.039 g, 0.084 mmol) in THF (0.5 mL). Additional THF (2×0.5 mL) wasused to aid in complete transfer of the sulfinamide. After 1.5 h,additional (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (1.00 mL, 0.500mmol) was added and the reaction temperature was allowed to reach toambient temperatures. After several hours, the reaction mixture wasdiluted aqueous saturated NH₄Cl and EtOAc. The aqueous layer wasextracted with EtOAc (2×), the combined organic phase was washed withwater (2×), dried over Na₂SO₄ and concentrated in vacuo to give a thickoil. The resultant oil was purified on Biotage system (gradient elution,12% MTBE:95% Hexanes to 100% MTBE) to deliver the (3R)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.016 g, 0.027 mmol, 31% yield) as a light white foam and(3S)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.021 g, 0.036 mmol, 43% yield) as a light white foam. (3R)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate:LC/MS m/z 579 [(M (³⁵Cl)+H]⁺ and m/z 581 [(M (³⁷Cl)+H]⁺ and(3S)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate:LC/MS m/z 579 [M+H]⁺.

2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid

(Compound 164).

To a solution of (3S)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate(0.310 g, 0.535 mmol) in MeOH (1.5 mL) was added a solution of HCl inDioxane (0.25 mL, 1.00 mmol, 4 M). After 30 min, the mixture wasconcentrated in vacuo and excess HCl was azeotropically removed usingCH₂Cl₂ (3×) to give the amino-ester as an oil.

The resultant amino-ester was diluted with CHCl₃ (3 mL) and TFA (0.20mL, 2.60 mmol) and the mixture was heated at reflux. After 24 h, thesolution was cooled to room temperature and concentrated to giveyellow-green oil. The titled imino-acid (0.344 g) was obtained as an oilthat was processed to the amide bond formation without furtherpurification. LC/MS m/z 401 [M+H]⁺.

2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)-N-ethylacetamide

(Compound 165).

To a cooled (−10° C.) solution of unpurified2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid (Compound 164; 0.344 g, 0.858 mmol) in CH₂Cl₂ (2 mL) was added Et₃N(1.5 mL, 10.8 mmol) and 2 M EtNH₂ (in THF) (2.60 mL, 5.20 mmol),followed by2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1.00 g, 2.63 mmol). After complete addition ofthe reagents, the reaction mixture was warmed to ambient temperaturesand stirred for 1 h. The mixture was concentrated and the resultantpaste was partitioned between MTBE and 1 N HCl. The aqueous layer wasextracted with MTBE (2×) and the combined organic layer were washed withsaturated NaHCO₃, water (2×), dried over Na₂SO₄, concentration gave alight yellow solids. The resultant solids were purified on Biotagesystem (gradient elution, 12% EtOAc:95% Hexanes to 75% EtOAc:25%Hexanes) to give off-white solids. The solids were diluted in CH₃CN (2.0mL) and water (0.50 mL), the solution was frozen and lyophilized to givethe titled compound as off-white amorphous solids (0.047 g, 0.110 mmol,13% yield). ¹H NMR (400 MHz, D6-Acetone) δ 7.50-7.30 (m, 5H), 4.35 (t,J=6.8 Hz, 1H), 3.42-3.16 (m, 4H), 2.46 (s, 3H), 2.44 (s, 3H), 1.70 (s,3H), 1.14 (t, J=7.3 Hz, 3H); LC/MS m/z 428 [M+H]⁺.

2-((6R)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid

(Compound 166).

The titled compound was synthesized according to the protocol outlinedabove for intermediate2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid starting from intermediate (3R)-tert-butyl3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate.LC/MS m/z 401 [M+H]⁺.

2-((6R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)-N-ethylacetamide

(Compound 167).

The titled example was synthesized according to the protocol outlinedabove for2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)-N-ethylacetamidestarting from intermediate2-((6R)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid. ¹H NMR (400 MHz, D6-Acetone) δ 7.50-7.30 (m, 5H), 4.35 (t, J=6.8Hz, 1H), 3.42-3.16 (m, 4H), 2.46 (s, 3H), 2.44 (s, 3H), 1.70 (s, 3H),1.14 (t, J=7.3 Hz, 3H); LC/MS m/z 428 [M+H]⁺.

(Tetrahydro-2H-pyran-4-yl)magnesium chloride

To a vigorously stirred suspension of Mg (0.500 g, 20.57 mmol) turningsand iodine (0.019 g, 0.075 mmol) in THF (5 mL) under N₂ (g) was added1,2-dibromoethane (0.10 mL, 1.160 mmol) and 10% of a solution of4-chlorotetrahydro-2H-pyran (1.00 mL, 9.24 mmol) in THF (5 mL). Themixture was heated to 60° C. and as the reaction mixture turned clearand Grignard initiation took place, the remainder of the solution of4-chlorotetrahydro-2H-pyran (1.00 mL, 9.24 mmol) in THF was added slowlyover 30 min. The reaction mixture was stirred at 65° C. for 2 h todeliver a solution of (tetrahydro-2H-pyran-4-yl)magnesium chloride inTHF. The Grignard solution was used without any further purification.

(6S)-tert-butyl6-(2-(tert-butoxy)-2-oxoethyl)-2,3,9-trimethyl-4-oxo-4H-isoxazolo[5,4-c]thieno[2,3-e]azepine-5(6H)-carboxylate

To a murky yellow solution of tert-butyl2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)acetatea form of intermediate 17, prepared according to Example 14 (0.209 g,0.577 mmol) and DMAP (0.007 g, 0.058 mmol) in THF (2.0 mL) was addedBoc₂O (0.166 mL, 0.715 mmol). After 30 min, the reaction mixture wasconcentrated in vacuo to give brown solids. The crude product waspurified on Biotage system (gradient elution 5% EtOAc:95% Hexanes to 10%EtOAc:90% Hexanes, then isocratic 10% EtOAc:90% Hexanes) to deliver thetitled product (8.61 g, 20.1 mmol, 88% yield) as white solids. LC/MS m/z563 [M+H]⁺.

(3S)-tert-Butyl3-((tert-butoxycarbonyl)amino)-3-(4-(4,5-dimethyl-2-(tetrahydro-2H-pyran-4-carbonyl)thiophen-3-yl)-3-methylisoxazol-5-yl)propanoate

To a cooled (−40° C.) solution of (6S)-tert-butyl6-(2-tert-butoxy-2-oxoethyl)-2,3,9-trimethyl-4-oxo-4H-isoxazolo[4,5-e]thieno[3,2-c]azepine-5(6H)-carboxylate(136 mg, 0.294 mmol) in THF (0.5 mL) was added(tetrahydro-2H-pyran-4-yl)magnesium chloride (1.05 mL, 0.882 mmol) inone-portion. After 5 min, the purple mixture was allowed to warm to rt.The pink reaction was quenched with 1 N HCl and the aqueous layer wasextracted with EtOAc (2×), washed with saturated NaHCO₃, dried overNa₂SO₄, and concentrated to give a yellow oil. The oil was purified onBiotage system (gradient elution 5% EtOAc:95% Hexanes to 30% EtOAc:70%Hexanes, then isocratic 30% EtOAc:70% Hexanes) to yield the titledcompound (0.148 g, 0.270 mmol, 92% yield) as a white foam. LC/MS m/z 571[M+Na]⁺

2-((6S)-2,3,9-trimethyl-4-(tetrahydro-2H-pyran-4-yl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide

(Compound 168).

To a solution of (3S)-tert-butyl3-(tert-butoxycarbonylamino)-3-(4-(4,5-dimethyl-3-(tetrahydro-2H-pyran-4-carbonyl)thiophen-2-yl)-3-methylisoxazol-5-yl)propanoate(68 mg, 0.124 mmol) in CHCl₃ (1.0 mL) was added TFA (0.477 mL, 6.20mmol) and the reaction mixture was heated at reflux for 3 h. The yellowreaction mixture is cooled to ambient temperatures, concentrated invacuo, and excess TFA is azeotropically removed using CHCl₃ (2×2 mL),followed by toluene (2×10 mL). The crude carboxylic acid is dried andused without further purification.

To a cooled (0° C.) solution of the carboxylic acid in DMF (1.0 mL) wassequentially added N,N-diisopropylethyl amine (0.100 mL, 0.573 mmol),NH₄Cl (0.024 g, 0.449 mmol), and COMU (0.080 g, 0.186 mmol). Aftercomplete addition the reaction mixture turned light orange and wasallowed to warm to room temperature. After complete consumption of theacid (as detected by LC-MS analysis), the reaction mixture was dilutedwith H₂O and MTBE. The aqueous phase was extracted with MTBE (3×) andthe combined organic phase was washed with H₂O (2×), brine, dried overNa₂SO₄, and concentrated to give a white foam. The foam was purified onBiotage system (gradient elution 15% EtOAc:85% Hexanes to 100% EtOAc),the volatile organics were removed, and the purified compound wassubsequently diluted with CH₃CN (10 mL) and H₂O (1 mL), and lyophilizedto give the titled compound (0.031 g, 0.084 mmol, 68% yield) as offwhite-amorphous solids. ¹H NMR (400 MHz, Acetone-d₆) δ 7.08 (br. s, 1H),6.28 (br. s, 1H), 4.12 (t, J=6.73 Hz, 1H), 3.90 (d, J=11.12 Hz, 1H),3.66 (d, J=10.82 Hz, 1H), 3.40 (dt, J=3.66, 11.19 Hz, 1H), 3.14-3.31 (m,3H), 2.89-3.00 (m, 1H), 2.45 (s, 3H), 2.41 (s, 3H), 2.31 (d, J=0.59 Hz,3H), 1.79-1.91 (m, 2H), 1.11 (d, J=12.29 Hz, 1H), 1.00 (dt, J=4.10,12.14 Hz, 1H); LC/MS m/z 374 [M+H]⁺.

Example 19 Synthesis of Compounds of Formula I Wherein Ar is Pyridine

The compounds of this example were prepared in the manner set forth inScheme 5, below. Appropriate modification of this scheme to produceother compounds of the invention will be readily apparent to those ofskill in the art.

Exemplary synthesis of compounds of Formula I wherein Ar is pyridine,and intermediates useful in such compound are set forth below.

(4-Chlorophenyl)(2-fluoro-4-iodopyridin-3-yl)methanol

To a solution of 2-fluoro-4-iodonicotinaldehyde (1.50 g, 5.98 mmol) inanhydrous THF (20 mL) at −78° C. was slowly added a solution of(4-chlorophenyl)magnesium bromide (1 M in Et₂O) (6.57 mL, 6.57 mmol).After 15 minutes at −78° C., the reaction was quenched with MeOHfollowed by saturated aqueous ammonium chloride, and the product wasextracted with CH₂Cl₂ (4×). The organic layers were combined, dried overa cotton plug and concentrated to dryness under vacuum. The residue wasused without any purification in the next step. LC/MS m/z 364 [M+H]⁺.

(4-Chlorophenyl)(2-fluoro-4-iodopyridin-3-yl)methanone

To a solution of (4-chlorophenyl)(2-fluoro-4-iodopyridin-3-yl)methanol(2.17 g, 5.98 mmol) in CH₂Cl₂ (100 mL) was added manganese dioxide(10.40 g, 120 mmol) at room temperature. The reaction was heated to 45°C. for 3 h before the heterogeneous mixture was filtered through a padof silica gel. The cake was rinsed with EtOAc, and the filtrate wasconcentrated to dryness under vacuum. The residue was used in the nextstep without any additional purification. LC/MS m/z 362 [M+H]⁺.

(4-Chlorophenyl)(2-fluoro-4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-3-yl)methanone

A procedure analogous to the synthesis of(4-Chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-4,5-dimethylthiophen-3-yl)methanonein Example 18 was followed. Haloaryl(4-chlorophenyl)(2-fluoro-4-iodopyridin-3-yl)methanone was used asstarting material. LC/MS m/z 347 [M+H]⁺.

(4-(5-(Azidomethyl)-3-methylisoxazol-4-yl)-2-fluoropyridin-3-yl)(4-chlorophenyl)methanone

A procedure similar to the synthesis of(2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanonein Example 16 was followed, except that DMF was substituted by a mixtureof acetonitrile and water; and that(4-Chlorophenyl)(2-fluoro-4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-3-yl)methanonewas used as starting material. LC/MS m/z 372 [M+H]⁺.

6-(4-Chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine

(Compound 169).

A procedure similar to that used to produce6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[c]isoxazolo[4,3-e]azepine inExample 16 was followed. Crude(4-(5-(azidomethyl)-3-methylisoxazol-4-yl)-2-fluoropyridin-3-yl)(4-chlorophenyl)methanonewas used as starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d,J=5.26 Hz, 1H), 7.80 (dd, J=1.14, 5.26 Hz, 1H), 7.45 (td, J=2.30, 8.70Hz, 2H), 7.38 (td, J=2.10, 8.70 Hz, 2H), 5.32 (d, J=13.50 Hz, 1H), 4.30(d, J=13.50 Hz, 1H), 2.57 (s, 3H); LC/MS m/z 328 [M+H]⁺.

The side product(4-(5-(aminomethyl)-3-methylisoxazol-4-yl)-2-fluoropyridin-3-yl)(4-chlorophenyl)methanonewas be converted to6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepinein a mixture of absolute EtOH and acetic acid (2:1 v/v) at 110° C. formore than 1 h.

6-(4-Chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine

(Compound 170).

To a solution of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine(0.030 g, 0.092 mmol) in MeOH (2 mL) was added sodium hydride (60%dispersed in mineral oil) (0.037 g, 0.915 mmol) at room temperature. Thereaction was stirred at room temperature for 15 min (or until the gasevolution stopped) before it was heated to 80° C. for 75 min in a sealedvial. The reaction was then concentrated to dryness under vacuum, andthe residue was purified by flash chromatography (hexane/EtOAc 19:1 to5:5) to give6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepineas a white solid (0.031 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=5.49Hz, 1H), 7.43 (d, J=5.26 Hz, 1H), 7.39 (td, J=2.10, 8.70 Hz, 2H), 7.26(td, J=2.10, 8.47 Hz, 2H), 5.24 (d, J=13.28 Hz, 1H), 4.11 (d, J=13.50Hz, 1H), 3.61 (s, 3H), 2.55 (s, 3H); LC/MS m/z 340 [M+H]⁺.

6-(4-Chlorophenyl)-7-isopropoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine

(Compound 171).

A procedure similar to6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepinewas followed, except that 2-propanol was used instead of MeOH. ¹H NMR(400 MHz, DMSO-d₆) δ 8.38 (d, J=5.49 Hz, 1H), 7.36-7.41 (m, 3H), 7.22(td, J=2.10, 8.47 Hz, 2H), 5.22 (d, J=13.28 Hz, 1H), 5.06 (spt, J=6.20Hz, 1H), 4.10 (d, J=13.28 Hz, 1H), 2.55 (s, 3H), 1.08 (d, J=5.95 Hz,3H), 0.62 (d, J=6.18 Hz, 3H); LC/MS m/z 368 [M+H]⁺.

6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amino

(Compound 172).

To a solution of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine(0.025 g, 0.076 mmol) in 1,4-dioxane (1 mL) was added concentratedammonium hydroxide (2.00 mL, 51.4 mmol) at room temperature. Thereaction was heated to 80° C. for 17 h before silica gel was added. Thesolvent was removed under vacuum, the dry silica gel was packed and theadsorbed product was purified by flash chromatography (hexane/EtOAc 6:4to 0:10) to give6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amineas an off-white solid (0.006 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d,J=5.26 Hz, 1H), 7.38 (td, J=2.20, 8.93 Hz, 2H), 7.34 (td, J=2.20, 8.47Hz, 2H), 6.94 (d, J=5.26 Hz, 1H), 5.91 (s, 2H), 5.21 (d, J=12.82 Hz,1H), 4.04 (d, J=13.05 Hz, 1H), 2.50 (s, 3H); LC/MS m/z 325 [M+H]⁺.

6-(4-Chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine

(Compound 173).

To6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine(0.020 g, 0.061 mmol) was added a solution of methylamine (33% in EtOH)(4 mL) at room temperature. The reaction was heated to 80° C. for 22 hbefore silica gel was added. The solvent was removed under vacuum, thedry silica gel was packed and the adsorbed product was purified by flashchromatography (hexane/EtOAc 8:2 to 2:8) to give6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amineas a white solid (0.014 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=5.26Hz, 1H), 7.35 (td, J=2.30, 8.93 Hz, 2H), 7.30 (td, J=2.30, 8.93 Hz, 2H),6.93 (d, J=5.26 Hz, 1H), 5.87 (q, J=4.35 Hz, 1H), 5.22 (d, J=12.82 Hz,1H), 4.03 (s, 1H), 2.61 (d, J=4.58 Hz, 3H), 2.50 (s, 3H); LC/MS m/z 339[M+H]⁺.

6-(4-Chlorophenyl)-N-ethyl-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine

(Compound 174).

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-aminewas followed, except that ethylamine was used instead of methylamine. ¹HNMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=5.26 Hz, 1H), 7.35 (td, J=2.10, 8.93Hz, 2H), 7.30 (td, J=1.80, 8.20 Hz, 2H), 6.91 (d, J=5.26 Hz, 1H), 5.80(t, J=5.49 Hz, 1H), 5.22 (d, J=12.82 Hz, 1H), 4.01 (d, J=12.82 Hz, 1H),3.20-3.29 (m, 1H), 2.98-3.09 (m, 1H), 2.50 (s, 3H), 0.72 (s, 3H); LC/MSm/z 353 [M+H]⁺.

6-(4-Chlorophenyl)-N,N,1-trimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine

(Compound 175).

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-aminewas followed, except that a solution of dimethylamine (2 M in MeOH) wasused instead of methylamine (33% in EtOH). ¹H NMR (400 MHz, DMSO-d₆) δ8.35 (d, J=5.04 Hz, 1H), 7.37 (d, J=8.70 Hz, 2H), 7.20 (d, J=8.70 Hz,2H), 7.14 (d, J=5.04 Hz, 1H), 5.28 (s, 1H), 4.25 (d, J=12.82 Hz, 1H),2.70 (s, 6H), 2.54 (s, 3H); LC/MS m/z 353 [M+H]⁺.

Example 20 Synthesis of Compounds of Formula I, Wherein Ar is Pyridone

Compounds of Formula I wherein Ar is pyridone are synthesized accordingto Scheme 6, below. Appropriate modification of this scheme to produceother compounds of the invention will be readily apparent to those ofskill in the art.

6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one

(Compound 176).

To a solution of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepinefrom Example 19 (0.244 g, 0.744 mmol) in 1,4-dioxane (5 mL) was added anaqueous solution of sodium hydroxide (1M) (5.00 mL, 5.00 mmol) at roomtemperature. The reaction was heated to 110° C. for 90 min, then cooledto room temperature before a saturated solution of ammonium chloride wasadded. The product was extracted with CH₂Cl₂ (repeated 4 times), and theorganic layers were combined, dried over sodium sulfate, filtered andconcentrated to dryness under vacuum. The product was purified twice byflash chromatography (hexane/EtOAc 8:2 to 1:9) to give6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-oneas a white solid (0.211 g). ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (br.s.,1H), 7.66 (d, J=6.64 Hz, 1H), 7.38 (d, J=8.00 Hz, 2H), 7.33 (d, J=8.47Hz, 2H), 6.60 (d, J=6.87 Hz, 1H), 5.19 (d, J=13.05 Hz, 1H), 4.07 (d,J=13.05 Hz, 1H), 2.50 (s, 3H); LC/MS m/z 326 [M+H]⁺.

6-(4-Chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one

(Compound 177).

To a solution of6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepin-7(8H)-one(0.070 g, 0.215 mmol) in acetonitrile (2 mL) were added cesium carbonate(0.210 g, 0.645 mmol) and iodomethane (16.09 μl, 0.258 mmol) at roomtemperature. The reaction was stirred at room temperature for 2 h beforeit was diluted with CH₂Cl₂ and filtered. The filtrate was concentratedto dryness under vacuum, and the residue was purified by flashchromatography (hexane/EtOAc 9:1 to 3:7) to give6-(4-chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-oneas an off-white solid (0.064 g) and6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepineas side product. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J=7.10 Hz, 1H),7.34 (d, J=2.06 Hz, 4H), 6.67 (d, J=7.10 Hz, 1H), 5.20 (d, J=13.05 Hz,1H), 4.06 (d, J=13.05 Hz, 1H), 3.43 (s, 3H), 2.51 (s, 3H); LC/MS m/z 340[M+H]⁺.

Substitutions on the pyridone ring were achieved following the generalstep set forth in Scheme 7, below.

4-(6-(4-Chlorophenyl)-1-methyl-7-oxo-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-8(7H)-yl)benzonitrile

(Compound 178).

6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepin-7(8H)-one(0.025 g, 0.077 mmol), 4-cyanophenylboronic acid (0.023 g, 0.153 mmol),copper(II) acetate (0.035 g, 0.192 mmol) and pyridine (1 mL) werecharged into a vial equipped with a stir bar. The reaction was heated to40° C. for 3 h in an open vial (to allow contact with air) before silicagel was added. Then the pyridine was removed under vacuum. The drysilica gel was packed and the adsorbed product was purified by flashchromatography (hexane/EtOAc 19:1 to 4:6) to give4-(6-(4-chlorophenyl)-1-methyl-7-oxo-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-8(7H)-yl)benzonitrileas an off-white solid (0.027 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d,J=6.87 Hz, 1H), 8.02 (td, J=2.10, 8.24 Hz, 2H), 7.66 (td, J=2.10, 8.70Hz, 2H), 7.49 (td, J=2.10, 8.47 Hz, 2H), 7.35 (td, J=2.30, 8.70 Hz, 2H),6.84 (d, J=7.32 Hz, 1H), 5.26 (d, J=13.28 Hz, 1H), 4.18 (d, J=13.05 Hz,1H), 2.56 (s, 3H); LC/MS m/z 427 [M+H]⁺.

6-(4-Chlorophenyl)-1-methyl-8-phenyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one

(Compound 179).

A procedure similar to4-(6-(4-chlorophenyl)-1-methyl-7-oxo-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-8(7H)-yl)benzonitrilewas followed, except that phenylboronic acid was used instead of4-cyanophenylboronic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, J=7.10Hz, 1H), 7.31-7.55 (m, 9H), 6.78 (d, J=7.10 Hz, 1H), 5.25 (d, J=13.05Hz, 1H), 4.18 (d, J=13.28 Hz, 1H), 2.55 (s, 3H); LC/MS m/z 402 [M+H]⁺.

Example 21 Synthesis of Compounds of Formula I Wherein Ar is SubstitutedPyridine

Compounds of Formula I wherein Ar is substituted pyridine weresynthesized according to Scheme 8. Appropriate modification of thisscheme to produce other compounds of the invention will be readilyapparent to those of skill in the art.

(2-Fluoro-4-iodopyridin-3-yl)methanol

To a solution of 2-fluoro-4-iodonicotinaldehyde (3.50 g, 13.94 mmol) inabsolute EtOH (56 mL) was added sodium borohydride (0.264 g, 6.97 mmol)at room temperature. The reaction was stirred at room temperature for 1h, followed by the slow addition of 1 M aqueous hydrochloric acid. Theproduct was extracted with CH₂Cl₂ (repeated four times), and the organiclayers were combined, dried over sodium sulfate, filtered andconcentrated to dryness. The aqueous phase was basified to pH 8-10 with2 M aqueous sodium hydroxide and extracted with diethylether (repeatedfour times). Then the organic layers were combined, dried over sodiumsulfate, filtered, combined with the previously obtained residue andconcentrated to dryness under vacuum. The residue was used without anypurification in the next step. LC/MS m/z 254 [M+H]⁺.

3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluoro-4-iodopyridine

To a solution of (2-fluoro-4-iodopyridin-3-yl)methanol (3.52 g, 13.91mmol) in CH₂Cl₂ (80 mL) at room temperature was sequentially addedimidazole (1.894 g, 27.8 mmol) and TBDMS-Cl (2.52 g, 16.69 mmol). Thereaction was stirred at room temperature for 1 h before diethylether wasadded and the insoluble salts were filtered. Silica gel was added to thefiltrate prior to the solvent removal under vacuum. The dry silica gelwas packed, and the adsorbed product was purified by flashchromatography (hexane/EtOAc 10:0 to 7:3) to give3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-4-iodopyridine as awhite solid (4.5 g). LC/MS m/z 368 [M+H]⁺.

(4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)methanol

A procedure similar to that used to synthesize (4-Chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-4,5-dimethylthiophen-3-yl)methanonein Example 18 was followed. LC/MS m/z 353 [M+H]⁺.

4-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazole-5-carbaldehyde

To a solution of(4-(3-((tert-butyldimethylsilyloxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)methanol(1.35 mg, 8.83 mmol) in CH₂Cl₂ (38 mL) at room temperature was addedmanganese dioxide (6.66 g, 77 mmol). The heterogeneous reaction washeated to 50° C. in a sealed tube for 2 h. The reaction was then cooledto room temperature and filtered. Then the solid was rinsed with EtOAcand the filtrate was concentrated to dryness under vacuum. The residuewas used without any purification in the next step. LC/MS m/z 351[M+H]⁺.

(S,E)-N-((4-(3-((tert-Butyldimethylsilyloxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide

A procedure analogous to general protocol for(S)-tert-Butylsulfinylimine formation in Example 14 was followed. LC/MSm/z 454 [M+H]⁺.

(3S)-tert-Butyl3-(4-(3-((tert-butyldimethylsilyloxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)-3-((S)-1,1-dimethylethylsulfinamido)propanoate

A procedure analogous to general protocol for Addition of(2-tert-Butoxy-2-oxoethyl)zinc(II) Chloride to(S)-tert-Butylsulfinylimine in Example 14 was followed. LC/MS m/z 570[M+H]⁺.

(3S)-tert-Butyl3-((S)-1,1-dimethylethylsulfinamido)-3-(4-(2-fluoro-3-(hydroxymethyl)pyridin-4-yl)-3-methylisoxazol-5-yl)propanoate

To a solution of (3S)-tert-butyl3-(4-(3-((tert-butyldimethylsilyloxy)methyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)-3-((S)-1,1-dimethylethylsulfinamido)propanoate(1.01 g, 1.76 mmol) in anhydrous THF (20 mL) at room temperature wasadded a solution of tetrabutylammonium fluoride (1M in wet THF) (2.21mL, 2.205 mmol). The reaction was stirred at room temperature for 1 hbefore MeOH and silica gel were added. The solvent was removed, the drysilica gel was packed and the adsorbed product was purified by flashchromatography (hexane/EtOAc 7:3 to 5:5) to give (3S)-tert-butyl3-((S)-1,1-dimethylethylsulfinamido)-3-(4-(2-fluoro-3-(hydroxymethyl)pyridin-4-yl)-3-methylisoxazol-5-yl)propanoateas a gummy solid (0.694 g). LC/MS m/z 456 [M+H]⁺.

(3S)-tert-Butyl3-amino-3-(4-(2-fluoro-3-(hydroxymethyl)pyridin-4-yl)-3-methylisoxazol-5-yl)propanoate

A procedure similar to the general protocol for HCl-mediated cleavage ofthe sulfinyl group in Example 14 was followed. LC/MS m/z 352 [M+H]⁺.

tert-Butyl2-((4S)-7-fluoro-1-methyl-6-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetate

To a solution of (3S)-tert-butyl3-amino-3-(4-(2-fluoro-3-(hydroxymethyl)pyridin-4-yl)-3-methylisoxazol-5-yl)propanoate(200 mg, 0.569 mmol) and TEMPO (4.45 mg, 0.028 mmol) in CH₂Cl₂ (5 mL) at0° C. was sequentially added potassium bromide (33.9 mg, 0.285 mmol) andan aqueous solution of sodium hypochlorite (−0.35M buffered to pH ˜8.6with sodium bicarbonate) (4.879 mL, 1.708 mmol). The reaction wasvigorously stirred (to produce an emulsion) at 0° C. for 45 min beforediluting with CH₂Cl₂. The product was extracted with CH₂Cl₂ (repeatedonce), with CH₂Cl₂/MeOH (95:5) (repeated once) and CH₂Cl₂/TFE (95:5)(repeated once). The organic layers were combined, dried over a cottonplug and concentrated to dryness under vacuum. The residue was purifiedby flash chromatography (Hexane/EtOAc 8:2 to 5:5) to give tert-butyl2-((4S)-7-fluoro-1-methyl-6-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetateas a solid (45 mg). LC/MS m/z 348 [M+H]⁺.

(4S)-tert-Butyl4-(2-(tert-butoxy)-2-oxoethyl)-7-fluoro-1-methyl-6-oxo-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine-5(6H)-carboxylate

A procedure analogous to that used to synthesize (6S)-tert-butyl6-(2-tert-butoxy-2-oxoethyl)-2,3,9-trimethyl-4-oxo-4H-isoxazolo[4,5-e]thieno[3,2-c]azepine-5(6H)-carboxylatein Example 18 was followed. LC/MS m/z 448 [M+H]⁺.

Mixture of (3S)-tert-butyl3-((tert-butoxycarbonyl)amino)-3-(4-(3-(4-chlorobenzoyl)-2-fluoropyridin-4-yl)-3-methylisoxazol-5-yl)propanoate

and(4S)-tert-butyl4-(2-(tert-butoxy)-2-oxoethyl)-6-(4-chlorophenyl)-7-fluoro-6-hydroxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine-5(6H)-carboxylate

A procedure analogous to that used to synthesize (3S)-tert-Butyl3-((tert-butoxycarbonyl)amino)-3-(4-(4,5-dimethyl-2-(tetrahydro-2H-pyran-4-carbonyl)thiophen-3-yl)-3-methylisoxazol-5-yl)propanoatein Example 18 was followed. LC/MS m/z 560 [M+H]⁺.

2-((4S)-6-(4-Chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetamide

(Compound 180).

A procedure similar to that used to synthesize2-((6S)-2,3,9-trimethyl-4-(tetrahydro-2H-pyran-4-yl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamidein Example 18 was followed. LC/MS m/z 385 [M+H]⁺.

2-((4S)-6-(4-chlorophenyl)-1-methyl-7-(methylamino)-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetamide

(Compound 181).

A procedure analogous to that used to synthesize6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-aminein Example 20 was followed. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=5.26Hz, 1H), 7.67 (br. s, 1H), 7.36 (d, J=8.70 Hz, 2H), 7.30 (d, J=8.70 Hz,2H), 7.04 (br. s, 1H), 6.95 (d, J=5.26 Hz, 1H), 5.76-5.91 (q, J=4.38 Hz,1H), 4.38 (t, J=7.30 Hz, 1H), 3.28 (dd, J=7.80, 15.50 Hz, 1H), 3.12 (dd,J=6.75, 15.68 Hz, 1H), 2.63 (d, J=4.58 Hz, 3H), 2.50 (s, 3H); LC/MS m/z396 [M+H]⁺.

Example 22 Synthesis of Compounds of Formula I Wherein R² is Hydrogenand R³ is —CH₂—NR′—C(O)—R

The synthesis of compounds of Formula I wherein R² is hydrogen and R³ is—CH₂—NR′—C(O)—R are exemplified below. Appropriate modification of thisscheme to produce other compounds of the invention will be readilyapparent to those of skill in the art.

N-(((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)methyl)acetamide

(Compound 182).

To a solution of2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid (Compound 164; 0.044 g, 0.110 mmol) in toluene (1.5 mL) was addedEt₃N (0.050 mL, 0.359 mmol) and diphenylphosphoryl azide (0.060 mL,0.278 mmol). The reaction mixture was heated to 80-90° C. After 30 min,LC-MS analysis indicated complete consumption of the acid. The reactionmixture was cooled to ambient temperatures and concentrated in vacuo togive the isocyanate as a thick paste.

To the crude isocyanate was introduced 1,4-dioxane (1 mL) and aqueous 1N NaOH (1.00 mL, 1.000 mmol) and subsequently heated to 90° C. After 60min, LC-MS analysis indicated complete consumption of starting material.The bi-phasic mixture was cooled to room temperature and the aqueouslayer was extracted with EtOAc (3×). The combined organic phase waswashed with water, dried over Na₂SO₄, and concentrated to give the freeamine as an orange oil.

The resultant amine was diluted with 1,4-dioxane (1 mL) followed bysequential addition of Et₃N (0.1 mL, 0.717 mmol) and acetic anhydride(0.05 mL, 0.530 mmol). After 1 h, the solution was concentrated in vacuoand the resultant oil was purified on Biotage system (gradient elution10% EtOAc:90% Hexanes to 80% EtOAc:20% Hexanes, then isocratic 80%EtOAc:20% Hexanes) to give the titled compound as product as whitesolids. The solids were diluted in CH₃CN (2.0 mL) and water (1.0 mL),the solution was frozen and lyophilized to yield the titled product(0.030 g, 0.072 mmol, 66% yield) as off-white amorphous solids. ¹H NMR(400 MHz, Acetone) δ 7.60 (br. s, 1H), 7.35-7.46 (m, 4H), 4.15 (br. s,2H), 4.04 (br. s, 1H), 2.47 (s, 3H), 2.43 (s, 3H), 1.91 (s, 3H), 1.69(s, 3H); LC/MS m/z 414 [M+H]⁺.

Methyl(((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)methyl)carbamate

(Compound 183).

To a solution of2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid (Compound 164; 0.047 g, 0.117 mmol) in toluene (1.5 mL) was addedEt₃N (0.100 mL, 0.717 mmol) and diphenylphosphoryl azide (0.080 mL,0.370 mmol). The reaction mixture was heated to 80° C. After 1 h, LC-MSanalysis indicated complete consumption of the carboxylic acid. Thereaction mixture was cooled to ambient temperatures and concentrated invacuo to give a thick paste.

To the paste was introduced 1,4-dioxane (5 mL), MeOH (5 mL) and aqueous1 N NaOH (5 mL) and the bi-phasic mixture was subsequently heated to 90°C. After 24 h, LC-MS analysis indicated complete consumption ofacyl-azide. The bi-phasic mixture was cooled to room temperature and theaqueous layer extracted with EtOAc (3×). The combined organic phase waswashed with water, dried over Na₂SO₄, and concentrated to give the freeamine as white solids. The solids were purified on Biotage system(gradient elution 10% EtOAc:90% Hexanes to 20% EtOAc:80% Hexanes) togive the titled product (0.005 g, 0.012 mmol, 10% yield) as whitesolids; ¹H NMR (400 MHz, D6-Acetone) δ 7.43 (s, 2H), 7.40 (s, 2H), 6.70(br. s, 1H), 4.00-4.22 (m, 3H), 3.58 (s, 3H), 2.47 (s, 3H), 2.44 (s,3H), 1.70 (s, 3H); LC/MS m/z 430 [M+H]⁺.

Example 23 Synthesis of Other Compounds of Formula I

The synthesis of other exemplary compounds of Formula I are set forthbelow.

2-((6S)-4-((4-Chlorophenyl)amino)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid

(Compound 184).

To a vial was added tert-butyl2-((6S)-4-chloro-2,3,9-trimethyl-6H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)acetate,a form of intermediate 18, prepared according to Example 14 (0.056 g,0.147 mmol), 4-chloroaniline (0.042 g, 0.333 mmol),((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (0.039 g, 0.168 mmol) and DMSO (0.5 mL). The vial was sealed andinitially heated to 125° C. for 3 h in the microwave reactor. LC-MSanalysis shows complete consumption of starting material and formationof the desired coupled product as a mixture of acid and ester. Thereaction mixture was subsequently heated at 145° C. for an additional 2h, at which time LC-MS analysis show conversion of all intermediates todesired acid. The solution was partitioned between MTBE and 1 N NaOH.The organic layer was washed with additional 1 N NaOH (2×) and thecombined aqueous layer was acidified to with concentrated HCl. Theacidic aqueous layer (pH ˜3-4) was extracted with EtOAc (4×). Thecombined organic phase was washed with water (2×), brine (1×), driedover Na₂SO₄, and concentrated to yield the titled product (0.056 g,0.135 mmol, 92% yield) as a brown foam that was used without furtherpurification. LC/MS m/z 416 [M+H]⁺.

2-((6S)-4-((4-Chlorophenyl)amino)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide

(Compound 185).

To a solution of crude carboxylic acid in DMF (1.0 mL) was sequentiallyadded N,N-diisopropylethyl amine (0.100 mL, 0.573 mmol), NH₄Cl (0.028 g,0.523 mmol), and1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate ((“COMU”), Sigma-Aldrich) (0.038 g, 0.089 mmol).After complete addition of reagents the reaction mixture was allowed toage until complete consumption of the carboxylic acid was detected byLC-MS. The reaction mixture was dilute with EtOAc and brine. The aqueouslayer was extracted with EtOAc (3×) and the combined organic extract waswashed with water (2×), dried over Na₂SO₄ and concentrated to give apink oil. The oil was purified on Biotage system (gradient elution 10%EtOAc:90% Hexanes to 80% EtOAc:20% Hexanes, then isocratic 80% EtOAc:20%Hexanes), the volatile organics were removed, and the purified compoundwas subsequently diluted with CH₃CN (10 mL) and H₂O (1 mL), andlyophilized to give the titled compound (0.023 g, 0.055 mmol, 41.2%yield) as off white-amorphous solids. ¹H NMR (400 MHz, Acetone-d₆) δ7.80 (d, J=8.78 Hz, 2H), 7.21 (d, J=8.78 Hz, 2H), 7.12 (br. s, 1H), 6.35(br. s, 1H), 4.40 (br. s, 1H), 3.03-3.19 (m, J=8.50 Hz, 2H), 2.44 (s,3H), 2.40 (s, 3H), 2.31 (s, 3H); LC/MS m/z 415 [M+H]⁺.

2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide

(Compound 186).

A mixture of tert-butyl2-((6S)-4-chloro-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate,a form of intermediate 18, prepared according to Example 14 (0.220 g,0.58 mmol) and phenol (0.276 g, 2.90 mmol) in pyridine (1 mL) was heatedat 130° C. for 1 h by MW. After the solvent was removed in vacuo, theresidue was washed with 1 N NaOH, dried by anhydrous Na₂SO₄. The productwas purified by Prep-TLC (PE:EA=4:1) to give tert-butyl2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate(0.020 g, 7.9% yield) as a white solid. tert-butyl2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetatewas converted to target compound2-((6S)-2,3,9-trimethyl-4-phenoxy-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamideusing Step L in Example 14. ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.34 (m, 2H),7.22-7.07 (m, 3H), 6.07 (s, 1H), 5.18 (s, 1H), 4.46 (q, J=4.5 Hz, 1H),2.99-2.84 (m, 2H), 2.48 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H); LC/MS m/z382 [M+H]⁺.

(6S)-6-((1H-imidazol-2-yl)methyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepine

(Compound 187).

To a solution of2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetamide(Compound 110, 0.120 g, 0.30 mmol) in THF (5 mL) was added Lawessonreagent (0.248 g, 0.60 mmol). The mixture was refluxed overnight. Thereaction mixture was concentrated in vacuo and the residue wasrecrystallized by petroleum and ethyl acetate to give2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)ethanethioamide(0.080 g, 64% yield).

To a solution of2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)ethanethioamide(0.080 g, 0.19 mmol) and 2,2-dimethoxyethanamine (0.200 g, 1.90 mmol) inCH₃CN (5 mL) was added HgCl₂ (0.515 g, 1.90 mmol). The mixture wasrefluxed overnight. The reaction mixture was filtered, concentrated invacuo and the residue was purified by column chromatography (silica-gel,petroleum:ethyl acetate=2:1) to give(6S)-6-((1H-imidazol-2-yl)methyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepineas a yellow solid (0.005 g, 6.2% yield): ¹H NMR (300 MHz, DMSO-d₆) δ8.26 (br, 1H), 7.42 (d, J=4.8 Hz, 2H), 7.24 (d, J=4.8 Hz, 2H), 6.82 (d,J=1.2 Hz, 2H), 4.40-4.30 (m, 1H), 3.84-3.74 (m, 2H), 2.50 (s, 3H), 2.42(s, 3H), 1.64 (s, 3H); LC/MS m/z 423 [M+H]⁺.

(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6-(thiazol-2-ylmethyl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepine

(Compound 188).

To a solution of2-((6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)aceticacid (Compound 164; 0.160 g, 0.40 mmol) and DMF (1 drop) indichloromethane (2 mL) was added oxalyl chloride (0.070 g, 0.55 mmol)drop-wise at 0° C. The mixture was stirred for 0.5 hour at roomtemperature. The solution was cooled to 0° C. and2,2-dimethoxyethanamine (0.210 g, 5.00 mmol) was added. The mixture wasstirred for 0.5 hour at room temperature. Then the solution was dilutedwith water (5 mL) and extracted with ethyl acetate (10 mL×3). Thecombined organic layers were washed with 1 N HCl and NaHCO₃, dried overNa₂SO₄, concentrated in vacuo to give2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)-N-(dimethoxymethyl)acetamideas a light yellow solid (0.120 g, yield 63.4%) which was used directlyin the next step without further purification.

To a solution of2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)-N-(dimethoxymethyl)acetamide(0.120 g, 0.25 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (2 mL, 26 mmol). The reaction mixture was stirred for 5 h. Themixture was concentrated and THF (5 mL) and Lawesson reagent (0.248 g,0.60 mmol) were added. The mixture was refluxed overnight. The reactionmixture was concentrated in vacuo and the residue was purified by columnchromatography (silica-gel, petroleum:ethyl acetate=10:1) to give(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6-(thiazol-2-ylmethyl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepineas a yellow solid (0.030 g, 17% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.73(d, J=3.3 Hz, 1H); 7.35-7.29 (m, 5H), 4.31-4.20 (m, 3H), 2.51 (s, 3H),2.40 (s, 3H), 1.64 (s, 3H); LC/MS m/z 440 [M+H]⁺.

Example 24 IC50 Measurements for Inhibitors Using BRD4 AlphaLisa BindingAssay

His/Flag epitope tagged BRD4 BD1₄₂₋₁₆₈ was cloned, expressed andpurified to homogeneity. BRD4 binding and inhibition was assessed bymonitoring the engagement of biotinylated H4-tetraacetyl peptide(Millipore #12-379) with the target using the AlphaLisa technology(Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD4(BD1) (30 nMfinal) was combined with peptide (200 nM final) in 40 mM HEPES (pH 7.0),40 mM NaCl, 1 mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 eitherin the presence of DMSO (final 1.2% DMSO) or compound dilution series inDMSO. After 20 minute incubation at room temperature Alpha streptavidindonor beads and AlphaLisa anti-Flag acceptor beads were added to a finalconcentration of 10 ug/mL each. After three hours equilibration plateswere read on an Envision instrument and IC₅₀s calculated using a fourparameter non-linear curve fit. The results of this assay are set forthin Table 6, below.

TABLE 6 Activity of Exemplary Compounds of the Invention Compound No.BRD4 Alphascreen IC₅₀ 100 + 101 + 102 + 103 + 104 ++ 105 +++ 106 + 107 +108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 +120 + 121 +++ 122 +++ 123 +++ 124 + 125 +++ 126 + 127 +++ 128 + 129 +130 + 131 + 132 + 133 + 134 + 135 + 136 + 137 + 138 + 139 + 140 + 141 +142 + 143 + 144 + 145 + 146 + 147 + 148 + 149 + 150 + 151 + 152 +++ 153+++ 154 +++ 155 + 156 + 159 + 160 + 162 + 163 + 165 + 167 +++ 168 +++169 +++ 170 + 171 +++ 172 + 173 + 174 + 175 + 176 +++ 177 +++ 178 +++179 +++ 181 + 182 + 183 + 185 +++ 186 ++ 187 + 188 + 189 +++ 190 + 191+++ In Table 6, “+” represents a value under 0.50 μM; “++” a valuebetween 0.50 μM and 1 μM; and “+++” a value greater than 1 μM.

Example 25 Cell-Based Assays

cMyc RNA Quantification Assay (QuantiGene® Assay):

MV4:11 (AML) or Raji (Burkitt's lymphoma) cells were seeded in a 96-wellplate and incubated in the presence of various concentrations ofcompounds for 4 h. Relative mRNA levels were quantitated by usingQuantiGene 2.0 assay (Affymetrix) according to the manufacturer'srecommendation. Signals were detected by using an Envision plate reader(Perkin-Elmer). Biological duplicates were averaged and normalized tovehicle (DMSO) control to calculate percent MYC mRNA levels.

Cell-Based IL-6 Quantification Assay (ELISA, Mesoscale Assay):

100,000 THP-1 cells were seeded in RPMI1640-10% FBS in 96-well plates.LPS (E. Coli Invitrogen) in RPMI-10% FBS at a final concentration of 4μg/mL was added to the wells and the cells are then incubated in thepresence of various concentrations of compounds for 16 h. Plates arespun (2 rpm, 5 min), an aliquot of 25 uL supernatant is transferred into an ELISA plate (Mesoscale technology, MSD) and the detection of IL-6is performed using manufacturer's instructions. The amount of cells ineach well is assessed using CellTiter-Glo® (Promega). The ratio of ELISAvalue/CellTiter-Glo value is used to calculate the percent of inhibitionof IL-6 secretion. The result of these assays for certain compounds ofthe invention are set forth in Table 7 below.

Cmpd No. IL6 MYC-Raji MYC-MV411 100 ++ n.t. n.t. 101 ++ n.t. n.t.102 + + n.t. 103 + + n.t. 104 ++ n.t. n.t. 105 +++ n.t. n.t. 106 + n.t.n.t. 107 + n.t. n.t. 108 + + n.t. 109 + + n.t. 110 + + + 111 + n.t. n.t.112 + + n.t. 113 + + n.t. 114 + + n.t. 115 + + n.t. 116 + + n.t. 117 +n.t. n.t. 118 + + n.t. 119 ++ n.t. n.t. 120 + ++ n.t. 121 +++ n.t. n.t.122 +++ n.t. n.t. 123 +++ n.t. n.t. 124 ++ +++ n.t. 125 +++ n.t. n.t.126 + +++ n.t. 127 +++ n.t. n.t. 128 + + n.t. 129 + + n.t. 130 + + +131 + + n.t. 132 + + + 133 + ++ n.t. 134 + ++ n.t. 135 + + n.t.136 + + + 137 + ++ n.t. 138 + + n.t. 139 + + + 140 + + n.t. 141 + +++n.t. 142 + ++ n.t. 143 + ++ n.t. 144 + + + 145 + + + 146 + + n.t. 147 +++ n.t. 148 + + + 149 + + n.t. 150 + + n.t. 151 + n.t. n.t. 152 +++ +++n.t. 153 +++ n.t. n.t. 154 +++ n.t. n.t. 155 ++ + n.t. 156 +++ n.t. n.t.159 + + n.t. 160 + + n.t. 162 +++ n.t. n.t. 163 + +++ n.t. 165 + + n.t.168 +++ n.t. n.t. 169 +++ n.t. n.t. 170 +++ n.t. n.t. 171 +++ n.t. n.t.172 + ++ n.t. 173 + + n.t. 174 + ++ n.t. 175 ++ +++ n.t. 176 +++ n.t.n.t. 177 +++ n.t. n.t. 178 +++ n.t. n.t. 179 +++ n.t. n.t. 180 + ++ ++181 + + + 182 ++ n.t. n.t. 183 ++ n.t. n.t. 185 +++ n.t. n.t. 186 ++ +++n.t. 187 +++ +++ n.t. 188 + +++ n.t. In Table 7, “n.t.” = not tested,“+” represents a value under 0.50 μM; “++” a value between 0.50 μM and 1μM; and “+++” a value greater than 1 μM.

Example 26 Preparation of Compounds of Formula II, Where R⁵ is Aryl orHeteroaryl

Scheme 9, below sets forth a general method for making certain compoundsof the invention.

General Procedure for Imide 30 Formation (Step M).

To a solution of lactam starting material (intermediate 17 wherein ringA is aryl or heteroaryl and (R⁵)_(n) is a single halo substituent; 1equivalent) and DMAP (0.10 equivalent or 10 mol %) in THF (0.5 M insubstrate concentration) was added Boc₂O (1.2-1.3 equivalent). After 30min, the reaction mixture was concentrated in vacuo to yield brownsolids. The crude product may either be purified on Biotage system(gradient elution 5% EtOAc: 95% Hexanes to 10% EtOAc:90% Hexanes, thenisocratic 10% EtOAc:90% Hexanes) or crystallized from EtOAc:Hexanesmixtures to deliver the titled N-Boc imide product 30 (generally in therange of 88% to 97% yield) as white solids.

General Procedure for Addition of Nucleophiles to N-Boc-Imide 30 (StepN).

To a cooled (−40° C.) solution of N-Boc-Imide 30 (1 equivalent) in THF(0.5 M in substrate concentration) was added the appropriate Grignardreagent (typically 1.1-1.5 equivalent) in one-portion. After 5 min, themixture was allowed to warm to room temperature and quenched with 1 NHCl. The aqueous layer was extracted with EtOAc (2×). The combinedorganic extracts were washed with aqueous saturated NaHCO₃, dried overNa₂SO₄, and concentrated in vacuo. The crude product was purified onBiotage system (typically gradient elution 5% EtOAc:95% Hexanes to 30%EtOAc:70% Hexanes) to yield the desired N-Boc ketone compound 31(generally >90% yield) generally as a either a white foam or solids.

General Procedure for TFA-Deprotection and Azepine 32 Formation (StepO).

To a solution of N-Boc ketone 31 in CHCl₃ (0.2 M in substrateconcentration) was added TFA (10-30 equivalent) and the reaction mixturewas heated at reflux for ˜24 h. The yellow reaction mixture is cooled toambient temperatures, concentrated in vacuo, and excess TFA wasazeotropically removed using excess CHCl₃, followed by toluene. Thecrude carboxylic acid 32 was dried and used without furtherpurification. The carboxylic acid 32 was converted to the correspondingcarboxamide 33 using a coupling reagent and an appropriate base asdescribed in Step L.

An alternative method to the coupling step described in Step L utilizedfor converting carboxylic acid 32 to the corresponding carboxamide 33(designated Step S) as follows. To a solution of carboxylic acid 32 (1equivalent) in anhydrous dichloromethane was added oxalyl chloride (25equivalents) in a dropwise manner. After stirring for 1 h, the mixturewas concentrated. The resulting residue was dissolved in dichloromethaneand 0.5 N ammonia in 1.4-dioxane (5 equivalents) was introduced. Afteraging for 2 h, the reaction mixture was concentrated in vacuo and theresulting residue was purified by flash column chromatography(silica-gel, dichloromethane:methanol=20:1) to give the desiredcarboxamide 33 product as a solid.

General Procedure for Suzuki Cross-Coupling to Aryl-halide (Step P).

To a re-sealable vial the carboxamide 33 from above (1.0 equivalent) wasadded Pd₂(dba)₃ (0.10 equivalent), tri-tert-butylphosphoniumtetrafluoroborate (0.22 equivalent), potassium phosphate tribasic,monohydrate (2.0 equivalent), and the appropriate aryl boronic acid orhetero-aryl boronic acid (1.5 equivalent). The flask was evacuated andpurged (3×), followed by sequential addition of 1,4-dioxane and water(typical ratio 20:1), and the flask was once again evacuated and purgedwith N₂ (g) (3×) and the reaction mixture was heated to 100° C. untilthe consumption of the aryl chloride was detected by LC-MS. The reactionmixture was subsequently cooled to room temperature and filtered over aplug of Celite. The filter cake was washed with EtOAc (3×) and thefiltrate was concentrated in vacuo. The cross-coupled product of FormulaII was purified via Biotage system (generally gradient elution usingmixtures of EtOAc-Hexanes) to yield the desired coupled product (in50-90% yield).

The compounds in Tables 8 and 9 were made using the general protocoldescribed above in Example 26 and/or the protocols described in Example14. The final steps employed from those Examples are indicated for eachcompound. Steps Q and R employed in the synthesis of Compounds 239, 248and 249 are described in the next example.

TABLE 8 Compound Final No. R₁₀ Physical Data steps 196

LC/MS m/z 351 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.45 (s, 1H), 7.99-7.94(m, 1H), 7.62-7.59 (m, 2H), 7.50-7.33 (m, 3H), 6.25 (br. s, 1H), 5.62(br. s, 1H), 4.62-4.58 (m,1H), 3.43-3.30 (m, 2H), 2.55 (s, 3H). H, L

TABLE 9 Compound No. R₅ R₁₁ Physical Data Final Steps 192 Cl CN LC/MSm/z 437 [M + H]⁺; ¹H H, L NMR (400 MHz, DMSO-d₆) δ 8.55-8.46 (m, 1H),7.91-7.83 (m, 3H), 7.82-7.75 (m, 1H), 7.50-7.43 (m, 2H), 7.42-7.37 (m,1H), 4.55-4.50 (m, 1H), 4.44-4.38 (m, 1H), 3.26-3.12 (m, 2H), 2.50 (br.s, 3H). 197 OCF₃ Cl LC/MS m/z 450 [M + H]⁺; ¹H H, L NMR (400 MHz,DMSO-d₆) δ 7.97 (d, J = 8.70 Hz, 1H), 7.77- 7.71 (m, 1H), 7.65 (br. s,1H), 7.48-7.43 (m, 2H), 7.36-7.30 (m, 3H), 7.05 (br. s, 1H), 4.40- 4.29(m, 1H), 3.23-3.12 (m, 2H), 2.51 (s, 3H). 201 Cl CF₃ LC/MS m/z 434 [M +H]⁺; ¹H H, L NMR (400 MHz, DMSO-d₆) δ 7.90-7.85 (m, 1H), 7.81-7.74 (m,3H), 7.67-7.62 (m, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 2.3 Hz,1H), 7.07-7.02 (m, 1H), 4.43-4.35 (m, 1H), 3.22- 3.11 (m, 2H), 2.50 (s,3H). 203 H CF₃ LC/MS m/z 399 [M + H]⁺; ¹H H, L NMR (300 MHz, Acetone-d₆)δ 7.86 (d, J = 7.8 Hz, 1H), 7.75- 7.69 (m, 3H), 7.60 (d, J = 8.4 Hz,2H), 7.44 (d, J = 8.1 Hz, 2H), 7.16 (m, 1H), 6.42-6.41 (m, 1H),4.54-4.52 (m, 1H), 3.35-3.31 (m, 2H), 2.58 (s, 3H). 206

CF₃ LC/MS m/z 492 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J = 2.5Hz, 1H), 7.99- 7.93 (m, 1H), 7.92-7.84 (m, 2H), 7.74 (d, J = 8.1 Hz,2H), 7.68 (br. s, 1H), 7.58-7.51 (m, 3H), 7.06 (br. s, 1H), 6.82 (br. s,2H), 6.67 (d, J = 8.9 Hz, 1H), 4.46-4.34 (m, 1H), 3.20 (br. s, 2H), 2.56(s, 3H). H, L, P 210 F Cl LC/MS m/z 384 [M + H]⁺; ¹H M, N, O NMR (400MHz, Acetone-d₆) δ 7.90 (dd, J = 5.56, 8.78 Hz, 1H), 7.57-7.48 (m, 1H),7.48-7.34 (m, 4H), 7.23 (dd, J = 2.93, 9.65 Hz, 1H), 7.14 (br. s, 1H),6.41 (br. s, 1H), 4.50 (br. s, 1H), 3.31 (d, J = 7.02 Hz, 2H), 2.53 (s,3H). 211 Cl F LC/MS m/z 384 [M + H]⁺; ¹H H, L NMR (400 MHz, DMSO-d₆) δ7.87-7.84 (m, 1H), 7.79-7.76 (m, 1H), 7.64 (br. s, 1H), 7.37- 7.32 (m,3H), 7.24-7.21 (m, 2H), 7.02 (br. s, 1H), 4.39-4.12 (m, 1H), 3.18 (m,2H), 2.47 (s, 3H). 212 F CN LC/MS m/z 375 [M + H]⁺; ¹H H, L NMR (400MHz, DMSO-d₆) δ 7.93-7.84 (m, 3H), 7.68-7.59 (m, 2H), 7.52-7.47 (m, 2H),7.22 (dd, J = 2.75, 9.61 Hz, 1H), 7.05 (br. s, 1H), 4.31-4.44 (m, 1H),3.18 (br. s, 2H), 2.50 (s, 3H). 213

Cl LC/MS m/z 458 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (d, J = 2.29Hz, 1H), 7.97- 7.90 (m, 1H), 7.88-7.83 (m, 1H), 7.81-7.75 (m, 1H), 7.70-7.62 (br. s, 1H), 7.53 (d, J = 1.83 Hz, 1H), 7.47-7.30 (m, 4H), 7.04(br. s, 1H), 6.49 (d, J = 8.93 Hz, 1H), 6.15 (br. s, 2H), 4.39- 4.31 (m,1H), 3.23-3.13 (m, 2H), 2.53 (s, 3H). M, P, N, O, L 216

F LC/MS m/z 442 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 8.07(br. s, 1H), 7.95 (m, 1H), 7.93 (m, 1H), 7.69 (br. s, 1H), 7.58 (s, 1H),7.40 (dd, J = 5.49, 8.70 Hz, 2H), 7.19 (t, J = 8.81 Hz, 2H), 7.05 (br.s, 1H), 6.85 (br. s, 1H), 4.41-4.26 (m, 1H), 3.20-3.15 (m, 2H), 2.53 (s,3H). H, L, P 217 OCH₃ Cl LC/MS m/z 396 [M + H]⁺; ¹H H, L NMR (400 MHz,DMSO-d₆) δ 7.79-7.73 (m, 1H), 7.64 (br. s, 1H), 7.45-7.42 (m, 2H), 7.37-7.32 (m, 2H), 7.31 (d, 1H), 7.02 (br. s, 1H), 6.86 (d, J = 2.75 Hz, 1H),4.39-4.12 (m, 1H), 3.74 (s, 3H), 3.15 (br. s, 2H), 2.47 (s, 3H). 224 CNCl LC/MS m/z 391 [M + H]⁺; ¹H P (Zn(CN)₂ NMR (400 MHz, DMSO-d₆) δ wasused as 8.13 (dd, J = 1.66, 8.31 Hz, 1H), the 8.00 (d, J = 8.31 Hz, 1H),7.89 nucleophile), (d, J = 1.25 Hz, 1H), 7.65 (br. s, H, L 1H),7.49-7.43 (m, 2H), 7.35- 7.30 (m, 2H), 7.05 (br. s, 1H), 4.36 (br. s,1H), 3.17 (br. s, 2H), 2.53 (s, 3H). 226 H

LC/MS m/z 388 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (s, 1H),7.72-7.67 (m, 1H), 7.66-7.62 (m, 1H), 7.44-7.35 (m, 2H), 7.21 (d, J =3.32 Hz, 4H), 7.04-7.00 (m, 1H), 5.97 (s, 1H), 4.30-4.22 (m, 1H), 3.20-3.11 (m, 2H), 2.51 (s, 3H), 1.12 (d, J = 2.49 Hz, 2H), 0.95 (d, J = 2.49Hz, 2H). H, L 233 H

LC/MS m/z 389 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, J = 7.69Hz, 1H), 7.72- 7.67 (m, 1H), 7.64 (br. s, 1H), 7.50 (d, J = 8.52 Hz,2H), 7.45- 7.36 (m, 2H), 7.23 (d, J =8.31 Hz, 2H), 7.02 (br. s, 1H),4.31- 4.24 (m, 1H), 3.16 (br. s, 2H), 2.51 (s, 3H), 1.35 (s, 6H). H, L234

F LC/MS m/z 470 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.99-12.84 (m,1H), 8.08 (dd, J = 1.97, 8.21 Hz, 1H), 8.02-7.92 (m, 3H), 7.79 (d, J =8.52 Hz, 2H), 7.68 (s, 2H), 7.42 (dd, J = 5.51, 8.83 Hz, 2H), 7.20 (t, J= 8.72 Hz, 2H), 7.05 (br. s, 1H), 4.40-4.33 (m, 1H), 3.16 (s, 2H), 2.55(s, 3H). H, L, P 235 H

LC/MS m/z 390 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, J = 7.69Hz, 1H), 7.70 (dt, J = 1.66, 7.37 Hz, 1H), 7.64 (br. s, 1H), 7.46-7.36(m, 4H), 7.23 (d, J = 8.52 Hz, 2H), 7.02 (br. s, 1H), 5.05 (br. s, 1H),4.27 (br. s, 1H), 3.16 (br. s, 2H), 2.51 (s, 3H), 1.39 (s, 6H). H, L 239OH Cl LC/MS m/z 382 [M + H]⁺; ¹H H, L, Q NMR (400 MHz, DMSO-d₆) δ9.95-9.83 (m, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H),7.38-7.26 (m, 2H), 7.17- 7.08 (m, 1H), 7.05-6.96 (m, 1H), 6.72 (d, J =2.5 Hz, 1H), 4.34-4.18 (m, 1H), 3.21-3.01 (m, 2H), 2.45 (s, 3H). 248 OEtCl LC/MS m/z 410 [M + H]⁺; ¹H H, L, Q, R NMR (400 MHz, Acetone-d₆) δ7.74 (d, J = 9.07 Hz, 1H), 7.47- 7.35 (m, 4H), 7.28 (dd, J = 2.78, 8.63Hz, 1H), 7.15-7.09 (br. s, 1H), 6.93 (d, J = 2.63 Hz, 1H), 6.38 (br. s,1H), 4.54-4.36 (m, 1H), 4.2-3.9 (m, 2H), 3.27 (br. s, 2H), 2.49 (s, 3H),1.33 (t, J = 6.87 Hz, 3H). 249 O^(i)Pr Cl LC/MS m/z 424 [M + H]⁺; ¹H H,L, Q, R NMR (400 MHz, Acetone-d₆) δ 7.73 (d, J = 8.78 Hz, 1H), 7.50-7.34 (m, 4H), 7.27 (dd, J = 2.63, 8.78 Hz, 1H), 7.17-7.07 (br. s, 1H),6.91 (d, J = 2.63 Hz, 1H), 6.36 (br. s, 1H), 4.68-4.55 (m, 1H),4.52-4.38 (m, 1H), 3.37- 3.17 (m, 2H), 2.49 (s, 3H), 1.28 (d J = 6.00Hz, 3H), 1.24 (d, J = 6 Hx, 3H).

Example 27 Preparation of Compounds of Formula II, where Ring a isPhenyl and R⁵ is Hydroxy or Alkoxy

This general preparation scheme is exemplified by using2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamideas starting material.

General Procedure for Synthesis of Compounds where Ring A is Phenol(Step Q)

A round bottom flask was charged with2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide(1 equivalent), a stirbar and dichloromethane (volume to makeconcentration 0.1M). The flask was cooled to 0° C. and BBr₃ (50equivalents) was added dropwise. The resulting suspension was allowed tostir and warm to room temperature over 16 h, then re-cooled to 0° C. forthe dropwise addition of methanol (20 mL). The solution wasconcentrated, then redissolved in EtOAc and washed with 1 M HCl. Theaqueous phase was extracted with EtOAc (2×); the combined organics werewashed with brine, dried (Na₂SO₄), filtered and concentrated. Theproduct phenol could be purified on silica gel or used directly in thenext reaction.

General Procedure for Synthesis of Compounds where Ring A isAlkoxy-Substituted Phenyl (Step R)

A re-sealable reaction vial was charged with2-((4S)-6-(4-chlorophenyl)-8-hydroxy-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide(1 equivalent), a stirbar and 4-methylpentan-2-one (volume to makeconcentration 0.1M). Potassium carbonate (3 equivalents) was added,followed by the appropriate alkyl iodide (2 equivalents). The tube washeated at 75° C. for 4 h, then poured into water and washed with EtOAc(3×). The combined organics were washed with brine, dried (Na₂SO₄),filtered and concentrated. The product ether was purified on silica gelor by reverse phase HPLC.

Example 28 Synthesis of(4S)-8-chloro-1,4-dimethyl-4,1-benzo[c]isoxazolo[4,5-e]azepin-6(5H)-one

The title compound was used as an alternative for intermediate 17 inScheme 9 and can be used with Steps M, N, O and P (but does not requirestep L).

Methyl 5-chloro-2-iodobenzoate

To a round bottomed flask was added NaHCO₃ (22.31 g, 266 mmol),5-chloro-2-iodobenzoic acid (25 g, 89 mmol), DMF, and MeI (11.07 mL, 177mmol). The reaction was stirred at room temperature overnight. Thereaction was diluted with water and EtOAc. The layers were separated andthe aqueous layer was extracted with EtOAc. The combined organic layerswere washed with water (3×) and brine before being dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified via Biotageto afford the titled compound (25.81 g, 87 mmol). LC/MS m/z 297 [M+H]⁺.

Methyl2-(5-((E)-(((S)-tert-butylsulfinyl)imino)methyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate

This intermediate was prepared using the protocol outlined for thesynthesis of intermediate 13 in Scheme 1, starting from methyl5-chloro-2-iodobenzoate. LC/MS m/z 383 [M+H]⁺.

5-chloro-2-(5-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-3-methylisoxazol-4-yl)benzoate

To a round bottomed flask was added methyl2-(5-((E)-((S)-tert-butylsulfinylimino)methyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate(4.18 g, 10.92 mmol) and toluene (50 mL) before the solution was cooledto −78° C. To this solution was added methylmagnesium bromide (8.58 mL,12.01 mmol) and the solution stirred at −78° C. for 1 h. To thissolution was added an additional amount of methylmagnesium bromide (4.9mL, 6.86 mmol) and the reaction stirred at −78° C. for 1.25 h. Thereaction was quenched with saturated aqueous NH₄Cl and the layersseparated. The aqueous phase was extracted with EtOAc. The combinedorganic phase was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage (EtOAc/hex) toafford the titled compound as the major component of a mixture ofdiastereomers (3.37 g, 8.45 mmol); LC/MS m/z 399 [M+H]⁺.

(4S)-8-chloro-1,4-dimethyl-4H-benzo[c]isoxazolo[4,5-e]azepin-6(5H)-one

To a round bottomed flask was added methyl5-chloro-2-(5-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-3-methylisoxazol-4-yl)benzoate(3.37 g, 8.45 mmol), MeOH (48 mL), and HCl [2M in ether] (8.45 mL, 16.90mmol). The reaction was stirred at room temperature for 30 min beforeconcentrating. The crude residue was concentrated from toluene (2×) andhexane (1×) before being placed on a high vacuum line overnight. Thecrude residue (as an off-white foam) was dissolved in THF (100 mL)before cooling to −78° C. and addition of isopropylmagnesium chloride(15 mL, 30.0 mmol). The solution was stirred at −78° C. for 5 min beforeremoval of the cold bath and warming the reaction to room temperature.The solution was quenched with saturated aqueous NH₄Cl and diluted withEtOAc. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford a white solid. Thismaterial was purified via chiral SFC to afford the titled compound (1.9g, 7.23 mmol); LC/MS m/z 263 [M+H]⁺.

Example 29 Synthesis of Compound 223

Synthesis of methyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate

To a solution of2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)aceticacid (100 mg, 0.27 mmol) and N,N-dimethylformamide (1 drop) indichloromethane (10 mL) was added oxalyl chloride (56 mg, 0.40 mmol)dropwise at 0° C. The mixture was stirred for 0.5 hour at roomtemperature. The solution was cooled to 0° C. and methanol (100 mL) wasadded. The mixture was stirred for 0.5 hour at room temperature. Themixture was concentrated in vacuo, and the residue was diluted withwater (5 mL), and extracted with ethyl acetate (10 mL×3). The combinedorganic layers were dried by sodium sulfate, concentrated in vacuo andthe residue was purified by column chromatography (silica-gel,petroleum:ethyl acetate=2:1) to give methyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(80 mg, 77%) as a light yellow solid. LC/MS m/z 380 [M+H]⁺.

Synthesis of1-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-2-methylpropan-2-ol(Compound 223)

To the solution of methyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(76.2 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was slowly addedmethyllithium (3N) (0.40 mL, 1.20 mmol) at 0° C. The mixture was stirredfor 0.5 h at 0° C., quenched with saturated ammonium chloride andextracted with ethyl acetate (3×10 mL). The combined organic phase waswashed with brine, dried over sodium sulfate and concentrated. Theresidue was purified by preparative-HPLC (isocratic acetonitrile:0.01%acetic acid water=65:35) to give1-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-2-methylpropan-2-ol(30 mg, 39%) as a white solid. LC/MS m/z 380 [M+H]⁺; ¹H NMR (300 MHz,CD₃Cl) δ 7.59-7.63 (m, 2H), 7.40-7.28 (m, 7H), 4.36-4.31 (m, 1H),2.91-2.82 (m, 1H), 2.55 (s, 3H), 2.30-2.35 (m, 1H), 1.29 (s, 3H), 1.24(s, 3H).

Other compounds of the invention were made following the generalprocedures in Examples 14 and 28 and are set forth in Table 10. Thefinal steps employed from those Examples are indicated for eachcompound.

TABLE 10 Compound Final No. R₅ R₁₁ R₃ Physical Data steps 199 H Cl

LC/MS m/z 412 [M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.64-7.62 (m, 2H),7.43-7.21 (m, 6H), 6.70 (br. s, 1H), 4.67-4.63 (m, 1H), 4.50-4.40 (m,2H), 3.76-3.59 (m, 2H), 3.42-3.20 (m, 2H), 2.60 (s, 3H). H, L 204 H Cl

LC/MS m/z 407 [M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.60 (m, 2H),7.40-7.26 (m, 6H), 6.02 (br. s, 1H), 4.65-4.50 (m, 1H), 4.20-4.13 (m,1H), 3.27-3.21 (m, 2H), 2.55 (s, 3H), 1.27-1.20 (m, 6H). H, L 205 H Cl

LC/MS m/z 422 [M + H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.66-7.61 (m, 2H),7.41-7.25 (m, 6H), 6.38 (br. s, 1H), 4.57-4.52 (m, 1H), 3.36-3.14 (m,2H), 2.56 (s, 3H), 1.47 (s, 9H). H, L 214 H Cl

LC/MS m/z 410 [M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.63-7.59 (m, 2H),7.40-7.32 (m, 6H), 6.88-6.82 (br. s,1H), 4.67- 4.62 (m, 1H), 3.78-3.68(m, 2H), 3.52-3.41 (m, 2H), 3.31-3.20 (m, 2H), 2.81-2.78 (m, 1H), 2.56(s, 3H). H, L 230 Cl F CH₃ LC/MS m/z 341 [M + H]⁺; H ¹H NMR (400 MHz,Acetone-d₆) δ 7.85 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 2.3, 8.5 Hz, 1H),7.51- 7.46 (m, 2H), 7.44 (d, J = 2.3 Hz, 1H), 7.17-7.10 (m, 2H), 4.16(br. s, 1H), 2.53 (s, 3H), 1.89 (d, J = 6.7 Hz, 3H). 231

F CH₃ LC/MS miz 399 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (d, J =2.5 Hz, 1H), 7.90 (dd, J = 1.7, 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H),7.64 (dd, J = 2.5, 8.7 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.47- 7.39 (m,2H), 7.19 (t, J = 8.9 Hz, 2H), 6.49 (d, J = 8.3 Hz, 1H), 6.14 (s, 2H),4.16 (br. s, 1H), 2.54 (s, 3H), 1.84 (d, J = 6.2 Hz, 3H). H, P 237

F CH₃ LC/MS m/z 427 [M + H]⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 8.05 (d, J= 8.1 Hz, 2H), 8.01 (dd, J = 2.0, 8.1 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H),7.64 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.48-7.43 (m, 2H),7.11 (t, J = 8.8 Hz, 2H), 4.19 (br. s, 1H), 2.61 (s, 3H), 1.93 (d, J =6.8 Hz, 3H). H, P

Example 30 Preparation of6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine-4-carbonitrile(Compound 215)

(E)-(2-(5-((benzhydrylimino)methyl)-3-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone

To a round bottomed flask was added4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde (3.86 g,11.85 mmol), DCM (50 mL), diphenylmethanamine (2.143 mL, 12.44 mmol),and Na₂SO₄ (5.05 g, 35.5 mmol). The reaction was stirred at roomtemperature overnight before being filtered and concentrated. The cruderesidue was purified via Biotage (EtOAc/hex) to afford the titledcompound (5.61 g, 11.43 mmol) as pale yellow foam. LC/MS m/z 491 [M+H]⁺.

2-(benzhydrylamino)-2-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)acetonitrile

To a round bottomed flask was added(E)-(2-(5-((benzhydrylimino)methyl)-3-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone(320 mg, 0.652 mmol), DCM (4.5 mL), and Yt(OTf)₃ (40.4 mg, 0.065 mmol).To this solution was added TMS-CN (175 μl, 1.304 mmol) and the reactionwas stirred overnight at room temperature. This solution was dilutedwith saturated aqueous NaHCO₃. The layers were separated and the aqueousphase was extracted with DCM. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The crude residue was purifiedvia Biotage (EtOAc/hex) to afford the titled compound (300 mg, 0.579mmol). LC/MS m/z 518 [M+H]⁺.

6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine-4-carbonitrile(Compound 215)

To a re-sealable vial was added2-(benzhydrylamino)-2-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)acetonitrile(16 mg, 0.031 mmol), DCE (0.5 mL), and TFA (0.5 mL, 6.49 mmol). The vialwas sealed and heated to 80° C. for 3.5 h before cooling to roomtemperature and concentrating. The crude residue was purified viaBiotage (EtOAc/hex) to afford the titled compound (9 mg, 0.027 mmol).

LC/MS m/z 334 [M+H]⁺; ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.77-7.63 (m,2H), 7.51-7.40 (m, 4H), 7.38-7.32 (m, 2H), 5.21-4.84 (m, 1H), 2.62 (s,3H).

Example 31 Preparation of6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine-4-carboxamide(Compound 218)

To a round bottomed flask was added6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine-4-carbonitrile(32 mg, 0.096 mmol) and conc. HCl (1 mL, 32.9 mmol). The reaction wasstirred at room temperature for 1 h and during this time a precipitateformed. This solution was diluted with water and the precipitate wascollected via filtration. Upon washing with water the precipitatedissolved. The layers were separated and the aqueous was extracted withether (3×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated. This crude mixture was taken upin DCE (1 mL) and TFA (1 mL, 12.98 mmol). The vial was sealed and thereaction heated to 80° C. for 1 h before cooling to room temperature andstirring for an additional 2 h. The solution was concentrated and thecrude residue was purified via Biotage (EtOAc/hex) to afford the titledcompound (16.2 mg, 0.046 mmol) as a white solid. LC/MS m/z 352 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.86 (m, 2H), 7.82 (d, J=7.8 Hz, 1H),7.71 (t, J=7.2 Hz, 1H), 7.52-7.47 (m, 2H), 7.46-7.36 (m, 4H), 4.73-4.42(m, 1H), 2.50 (s, 3H)

Example 32 Preparation of6-(4-fluorophenyl)-1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepine(Compound 238)

Ethyl2-(5-((S)-1-((S)-1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-3-methylisoxazol-4-yl)benzoate

To a round bottomed flask was added ethyl2-(5-((E)-((S)-tert-butylsulfinylimino)methyl)-3-methylisoxazol-4-yl)benzoate(200 mg, 0.552 mmol), THF, and TBAT (tetrabutylammoniumdifluorotriphenylsilicate) (357 mg, 0.662 mmol). The solution was cooledto −42° C. in an acetonitrile/dry-ice bath before addition oftrimethyl(trifluoromethyl)silane (131 μl, 0.883 mmol). The solution wasstirred at −42° C. before warming to −10° C. The solution was dilutedwith water and EtOAc before the layers were separated. The aqueous phasewas extracted with EtOAc and the combined organic phase was washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude residuewas purified via Biotage (EtOAc/hex) to afford the titled compound(182.4 mg, 0.422 mmol). LC/MS m/z 433 [M+H]⁺.

1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepin-6(5H)-one

To a round bottomed flask was added ethyl2-(5-((S)-1-amino-2,2,2-trifluoroethyl)-3-methylisoxazol-4-yl)benzoate(124.2 mg, 0.378 mmol) and THF (2 mL) before the solution was cooled to−40° C. To this solution was added isopropylmagnesium chloride (473 μl,0.946 mmol) and the reaction warmed to room temperature. The solutionwas diluted with NH₄Cl solution and EtOAc. The layers were separated andthe aqueous phase was extracted with EtOAc. The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude residue was purified via Biotage (EtOAc/hex) to afford the titledcompound (86 mg, 0.305 mmol). LC/MS m/z 283 [M+H]⁺.

6-chloro-1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepine

To a round bottomed flask was added1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepin-6(5H)-one(86 mg, 0.305 mmol), DCM (2 mL), and PCl₅ (102 mg, 0.488 mmol). Thesolution was stirred at room temperature for 30 min before addition ofmore PCl₅ (˜0.5 eq). The solution was stirred at room temperature for 4h before pouring onto an ice-saturated aqueous NaHCO₃ mixture. Thelayers were separated and the aqueous phase was extracted with DCM. Thecombined organic phase was dried over Na₂SO₄, filtered, andconcentrated. The crude residue was purified via Biotage (EtOAc/hex) toafford the titled compound (52.9 mg, 0.176 mmol). LC/MS m/z 301 [M+H]⁺.

6-(4-fluorophenyl)-1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepine(Compound 238)

To a resealable vial was added Pd(Ph₃P)₄ (20.33 mg, 0.018 mmol) and4-fluorophenylboronic acid (49.2 mg, 0.352 mmol) before the vial wassealed and evacuated/backfilled with N₂ (3×). To the vial was added6-chloro-1-methyl-4-(trifluoromethyl)-4H-benzo[c]isoxazolo[4,5-e]azepine(52.9 mg, 0.176 mmol) dissolved in toluene (500 μL) and Na₂CO₃ (2M, 176μl, 0.352 mmol). The solution was heated to 100° C. for 2 h beforecooling to room temperature and diluting with water and EtOAc. Thelayers were separated and the aqueous phase was extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified via Biotage(EtOAc/hex) to afford the titled compound (31.2 mg, 0.087 mmol). LC/MSm/z 361 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (d, J=7.1 Hz, 1H), 7.77(dt, J=1.7, 7.5 Hz, 1H), 7.52-7.41 (m, 4H), 7.29-7.21 (m, 2H), 5.38 (q,J=7.6 Hz, 1H), 2.56 (s, 3H).

Example 33 Synthesis of Compounds of the General Formula

Tert-butyl2-((6S)-2,3,9-trimethyl-4-(thiazol-4-yl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate(Step T)

A disposable reaction tube was charged with intermediate 18 from Scheme1, wherein ring A is thiophene (1 equivalent), thiazole (2 equivalents),palladium acetate (10 mol %), sodium acetate (2 equivalents) andN-methylpyrrolidone (volume to make concentration 0.1 M). The tube washeated to 90° C. for 16 hours. The mixture was diluted with water andextracted with ethyl acetate (3×10 mL). The organic phase was washedwith brine, dried over sodium sulfate, and concentrated. The residue waspurified by column chromatography (silica-gel, petroleum:ethylacetate=5:1) to give tert-butyl2-((6S)-2,3,9-trimethyl-4-(thiazol-4-yl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate(40 mg, 17.8% yield) as an off-white solid.

Synthesis of Compound 198

The resulting tert-butyl2-((6S)-2,3,9-trimethyl-4-(thiazol-4-yl)-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetateis then subjected to step L from Scheme 1 to form Compound 198.

Tert-butyl2-((6S)-4-isopropoxy-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-d]azepin-6-yl)acetate

A mixture of tert-butyl2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate(17 wherein ring A is thiophene; 100 mg, 0.276 mmol), silver oxide (70mg, 0.304 mmol) and 2-iodopropane (61 mg, 0.359 mmol) in toluene (5 mL)was heated to 90° C., and stirred overnight. After cooling to roomtemperature, the reaction mixture was evaporated to dryness and theresidue was purified by flash chromatography eluting with petroleumether/ethyl acetate=5:1 to give tert-butyl2-((6S)-4-isopropoxy-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetateas a yellow solid (80 mg, 72% yield). LC/MS m/z 404 [M+H]⁺; ¹H NMR (300MHz, CDCl₃) δ 5.30-5.03 (m, 1H), 4.51 (t, J=6 Hz, 1H), 3.11-3.08 (m,2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 1.46 (s, 9H), 1.30 (d,J=6 Hz, 3H), 1.20 (d, J=6 Hz, 3H).

Synthesis of Compound 193

Tert-butyl2-((6S)-4-isopropoxy-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetateis subjected to step L or deprotection followed by Step S to produceCompound 193.

Table 11, below, lists a number of compounds of the formula:

produced by the indicated steps.

TABLE 11 Com- pound Final No. R₁₀ Physical Data Steps 208

LC/MS m/z 434 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J = 8.24Hz, 2H), 7.63-7.68 (m, 1H), 7.46 (d, J = 8.01 Hz, 2H), 7.01-7.06 (m,1H), 4.25 (t, J = 7.40 Hz, 1H), 3.22 (d, J = 7.32 Hz, 2H), 2.45 (s, 3H),2.40 (s, 3H), 1.58 (s, 3H). H, L 236

LC/MS m/z 424 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (br. s, 1H),7.44 (d, J = 8.52 Hz, 2H), 7.19 (d, J = 8.10 Hz, 2H), 7.02 (br. s, 1H),5.11-4.99 (m, 1H), 4.18 (t, J = 7.17 Hz, 1H), 3.19 (dd, J = 3.84, 7.17Hz, 2H), 2.45 (s, 3H), 2.40 (s, 3H), 1.61 (s, 3H), 1.39 (d, J = 1.66 Hz,6H). H, L 195

LC/MS m/z 393 [M + H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 6.96-6.94 (m, 3H),6.63-6.60 (m, 2H), 4.93 (s, 1H), 4.58 (s, 1H), 4.24 (q, J = 6.9 Hz, 1H),4.17-4.11 (m, 1H), 3.41-3.35 (m, 1H), 3.27-3.22 (m, 1H), 2.39 (s, 3H),2.36 (s, 3H), 2.21 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H). J, L 198

LRMS m/z 373 [M + H]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1H), 7.62(s, 7.57 (s, 1H), 7.02 (s, 1H), 4.23-4.18 (m, 1H), 3.14-3.19 (m, 2H),2.46 (s, 3H), 2.44 (s, 3H), 1.92 (s, 3H). T, L 193

LC/MS m/z 347 [M + H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 6.46 (s, 1H), 5.86 (s,1H), 5.09-5.01 (m, 1H),4.45 (t, J = Hz, 1H), 3.06 (d, J = 6 Hz, 2H),2.43 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H), 1.33 (d, J = 6 Hz, 3H), 1.20(d, J = 6 Hz, 3H). L 194

LC/MS m/z 386 [M + H]⁺; ¹H NMR (300 MHz, CD₃OD) δ 4.80-4.85 (m, 1H),4.09-4.10 (m, 1H), 3.16-3.20 (m, 4H), 2.70-2.95 (m, 2H), 2.40-2.47 (m,9H), 2.31 (s, 3H), 2.07-2.08 (m, 2H), 1.33- 1.42 (m, 1H), 1.21-1.29 (m,1H). M, N, L

Example 34 Synthesis of ethyl(6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)carbamate(Compound 225) and its Enantiomers (Compounds 253 and 254)

Compound 225 was synthesized by the scheme set forth below:

6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine.

To a round bottom flask was added sodium hydride (0.13 g, 3.3 mmol, 60%in mineral oil). The flask was then purged with nitrogen, DMF (10 mL)was then added and the flask was cooled to 0° C.6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine (930 mg,3.0 mmol) in DMF (5 mL) was added and the reaction was allowed to stirfor 45 min. Trisyl azide (1.40 g, 4.5 mmol) in DMF (5 mL) was added andthe reaction was mixed at 0° C. for 1 h. The reaction poured into ether(100 mL) and washed with brine (3×). The organic layer was dried overNa₂SO₄, filtered, concentrated to afford crude4-azido-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine,which was used directly in the following reaction. LC/MS m/z 350 [M+H]⁺.

A round bottomed flask containing crude4-azido-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine(1.05 g, 3.0 mmol), was purged with nitrogen and diluted with THF (30mL) and water (6 mL). Trimethylphosphine (6.03 mL, 6.0 mmol, 1M intoluene) was added dropwise. The solution was stirred at ambienttemperature for 2 h. The reaction was poured into half-saturated brine(100 mL), extracted with EtOAc (3×), dried over Na₂SO₄, filtered,concentrated and purified on a Biotage system (isocratic elution 65%EtOAc: 35% Hexanes) to provide the title compound as an oil (0.44 g).LC/MS m/z 324 [M+H]⁺.

Ethyl(6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)carbamate(Compounds 225, 253 and 254).

To a round bottomed flask was added6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine(218 mg, 0.67 mmol). The flask was purged with nitrogen, MeCN was added(7 mL), and the solution was cooled to 0° C. Ethyl chloroformate (78 μL,0.81 mmol) and triethylamine (122 μL, 0.88 mmol) were added and thereaction was allowed to warm to ambient temperature and stirred for 2 h.The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO₃:brineand extracted with EtOAc. The organic layer was dried over Na₂SO₄,filtered, concentrated and purified on a Biotage (isocratic elution 25%EtOAc: 75% Hexanes) to provide the title compound as white solid (120mg).

The enantiomers were separated by chrial SFC using a 3.0×25.0 cmRegisPack column, with 35% cosolvent (1:1 MeOH:i-PrOH), 80 mL/min at 100bar. Rention time peak 1 (compound 253): 1.48 min, 100% ee. Retentiontime peak 2 (compound 254): 2.96 min, 98.1% ee.

The absolute configuration was not unambiguously determined but wasassigned based on the activity data in Table 14. LC/MS m/z 396 [M+H]⁺.

Example 351-(6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-3-ethylurea(Compound 245)

To a round bottomed flask was added6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine(218 mg, 0.67 mmol). The flask was purged with nitrogen, MeCN was added(7 mL), and the solution was cooled to 0° C. Ethyl isocyanate (128 μL,1.62 mmol) and triethylamine (244 μL, 1.75 mmol) were added and thereaction was allowed to warm to ambient temperature and stirred for 2 h.The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO₃:brineand extracted with EtOAc. The organic layer was dried over Na₂SO₄,filtered, concentrated and purified on a Biotage (isocratic elution 40%EtOAc: 60% Hexanes) to provide the title compound as white solid (220mg). LC/MS m/z 395 [M+H]⁺.

Example 36N-(6-(4-cyanophenyl)-1-methyl-4,1-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide(Compound 263)

To a round bottomed flask was added4-(4-amino-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-6-yl)benzonitrile(69 mg, 0.22 mmol) and DMAP (2.7 mg, 0.022 mmol). The flask was purgedwith nitrogen, MeCN was added (5 mL), and the solution was cooled to 0°C. Acetic anhydride (49.5 μL, 0.53 mmol) and triethylamine (79 μL, 0.57mmol) were added and the reaction was allowed to warm to ambienttemperature and stirred for 2 h. The reaction was quenched with a 1:1mixture of sat. aq. NaHCO₃:brine and extracted with EtOAc. The organiclayer was dried over Na₂SO₄, filtered, concentrated, and purified on aBiotage (isocratic elution 50% EtOAc: 50% Hexanes) to provide the titlecompound as white solid (64 mg). LC/MS m/z 357 [M+H]⁺.

Example 37N-(6-(4-cyanophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)isobutyramide(Compound 262)

To a round bottomed flask was added4-(4-amino-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-6-yl)benzonitrile(69 mg, 0.22 mmol) and DMAP (2.7 mg, 0.022 mmol). The flask was purgedwith nitrogen, acetonitrile (5 mL) was added (5 mL), and the solutionwas cooled to 0° C. Isobutyryl chloride (55 μL, 0.53 mmol) andtriethylamine (79 μL, 0.57 mmol) were added and the reaction was allowedto warm to ambient temperature and stirred for 2 h. The reaction wasquenched with a 1:1 mixture of sat. aq. NaHCO₃:brine and extracted withEtOAc. The organic layer was dried over Na₂SO₄, filtered, concentrated,and purified on a Biotage (isocratic elution 30% EtOAc: 70% Hexanes) toprovide the title compound as white solid (66 mg). LC/MS m/z 385 [M+H]⁺.

Data for each of the above compounds having the formula:

is set forth in Table 12, below.

TABLE 12 Compound No. R₁₁ R₁₂ Physical Data 225 Cl OEt LC/MS m/z 396[M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.07-9.01 (m, 1H), 7.84 (d, J =7.89 Hz, 1H), 7.74 (d, J = 1.45 Hz, 1H), 7.49-7.33 (m, 6H), 5.55- 5.50(m, 1H), 4.07 (d, J = 7.06 Hz, 2H), 2.52 (s, 3H), 1.21 (t, J = 7.06 Hz,3H). 245 Cl NHEt LC/MS m/z 395 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.84 (d, J = 7.69 Hz, 1H), 7.76-7.70 (m, 1H), 7.55 (d, J = 8.10 Hz, 1H),7.48-7.39 (m, 4H), 7.36-7.31 (m, 2H), 6.25 (t, J = 5.61 Hz, 1H), 5.61(d, J = 9.14 Hz, 1H), 3.13-3.04 (m, 2H), 2.52 (s, 3H), 1.03 (t, J = 7.17Hz, 3H). 259 OCF₃ NHEt LC/MS m/z 445 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ 7.85 (d, J = 7.69 Hz, 1H), 7.74 (dt, J = 1.66, 7.48 Hz, 1H), 7.55 (d,J = 8.93 Hz, 1H), 7.49-7.41 (m, 3H), 7.39-7.34 (m, 2H), 6.26 (t, J =5.61 Hz, 1H), 5.63 (d, J = 8.93 Hz, 1H), 3.13-3.04 (m, 2H), 2.52 (s,3H), 1.03 (t, J = 7.17 Hz, 3H). 260 F NHEt LC/MS m/z 379 [M + H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 7.84 (dd, J = 0.62, 7.89 Hz, 1H), 7.73 (dt, J =1.66, 7.48 Hz, 1H), 7.53 (d, J = 8.72 Hz, 1H), 7.48-7.33 (m, 4H),7.24-7.16 (m, 2H), 6.25 (t, J = 5.61 Hz, 1H), 5.60 (d, J = 8.93 Hz, 1H),3.13-3.04 (m, 2H), 2.52 (s, 3H), 1.03 (t, J = 7.17 Hz, 3H) 263 CN CH₃LC/MS m/z 357 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (d, J = 7.89Hz, 1H), 7.90-7.84 (m, 3H), 7.75 (dt, J = 1.35, 7.63 Hz, 1H), 7.55-7.50(m, 2H), 7.46 (dt, J = 1.25, 7.58 Hz, 1H), 7.40- 7.35 (m, 1H), 5.78 (d,J = 7.89 Hz, 1H), 2.53 (s, 3H), 2.06-2.02 (m, 3H). 264 CN ^(i)Pr LC/MSm/z 385 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (d, J = 8.10 Hz, 1H),7.90-7.84 (m, 3H), 7.79-7.73 (m, 1H), 7.55-7.50 (m, 2H), 7.49-7.43 (m,1H), 7.40-7.35 (m, 1H), 5.78 (d, J = 8.10 Hz, 1H), 2.71 (quin, J = 6.80Hz, 1H), 2.53 (s, 3H), 1.13-1.05 (m, 6H). 261 CN NHEt LC/MS m/z 386 [M +H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.88-7.83 (m, 3H), 7.77-7.72 (m, 1H),7.59 (d, J = 9.14 Hz, 1H), 7.51-7.43 (m, 3H), 7.40-7.36 (m, 1H), 6.26(t, J = 5.61 Hz, 1H), 5.67 (d, J = 8.93 Hz, 1H), 3.13-3.04 (m, 2H), 2.52(s, 3H), 1.03 (t, J = 7.17 Hz, 3H). 262 CN NH^(i)Pr LC/MS m/z 400 [M +H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.88-7.83 (m, 3H), 7.77-7.72 (m, 1H),7.51-7.42 (m, 4H), 7.40-7.35 (m, 1H), 6.18 (d, J = 7.48 Hz, 1H), 5.67(d, J = 8.93 Hz, 1H), 3.71 (dd, J = 6.65, 13.92 Hz, 1H), 2.52 (s, 3H),1.08 (t, J = 6.65 Hz, 6H).

Example 386-(4-Chlorophenyl)-1-methyl-7-phenoxy-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine(Compound 229)

A procedure similar to6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine(Compound 170) was followed, except that phenol was used instead ofmethanol. LC/MS m/z 402 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (d,J=5.40 Hz, 1H), 7.56 (d, J=5.40 Hz, 1H), 7.41 (s, 4H), 7.31 (tt, J=2.20,8.00 Hz, 2H), 7.14 (tt, J=1.40, 7.50 Hz, 1H), 6.79 (d, J=8.00 Hz, 2H),5.31 (d, J=13.3 Hz, 1H), 4.25 (d, J=13.29 Hz, 1H), 2.58 (s, 3H).

Example 39 Synthesis of5-(4-Chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine(Compound 219) and Related Compounds

Methyl 2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-6-methoxynicotinate

General procedures set forth in Scheme 1 were used to prepare thisintermediate from commercially available methyl2-chloro-6-methoxynicotinate. LC/MS m/z 279 [M+H]⁺.

2-Methoxy-10-methyl-6,7-dihydro-5H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-5-one

A reaction sequence similar to that used to prepare Compound 191 wasfollowed, except that methyl2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-6-methoxynicotinate was usedas starting material instead of(4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanoneand methanol was used as the cosolvent for the conversion of the azideto the lactam. LC/MS m/z 246 [M+H]⁺.

5-(4-Chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine(Compound 219)

General procedures set forth in Scheme 1 were used to prepare the titlecompound from2-methoxy-10-methyl-6,7-dihydro-5H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-5-one.More precisely, the protocol Step H (Suzuki coupling reaction) wasfollowed. LC/MS m/z 340 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (d,J=8.70 Hz, 1H), 7.45 (td, J=2.30, 8.80 Hz, 2H), 7.37 (td, J=2.30, 8.80Hz, 2H), 6.81 (d, J=8.70 Hz, 1H), 4.71 (br. s, 2H), 4.02 (s, 3H), 2.62(s, 3H).

2-Chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine(Compound 227)

To5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine(0.050 g, 0.147 mmol) were added phosphoryl chloride (1 mL, 11 mmol) andDMF (0.1 mL) at room temperature. The reaction was heated to 140° C. for4 h using microwave irradiation before 2M aq. NaOH and 2M aq. Na₂CO₃were added to quench the excess of reagent. The desired product wasextracted using EtOAc (repeated 4 times). The organic layers werecombined, dried over Na₂SO₄ and concentrated to dryness. A fraction ofthe residue was purified by reverse phase chromatography to give thetitle product as a white solid. LC/MS m/z 344 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 7.80 (d, J=8.52 Hz, 1H), 7.49 (d, J=8.31 Hz, 1H), 7.46 (td,J=2.10, 8.70 Hz, 2H), 7.41 (td, J=2.10, 8.70 Hz, 2H), 4.80 (s, 2H), 2.56(s, 3H).

5-(4-Chlorophenyl)-N,10-dimethyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine(Compound 221)

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-aminewas followed, except that2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepinewas used as starting material instead of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine.LC/MS m/z 339 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (td, J=2.30, 8.70Hz, 2H), 7.39-7.35 (m, 3H), 7.22 (d, J=8.72 Hz, 1H), 6.41 (d, J=8.93 Hz,1H), 4.63 (br. s, 2H), 2.91 (d, J=4.57 Hz, 3H), 2.58 (s, 3H).

5-(4-Chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine(Compound 228)

To a solution of2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine(0.050 g, 0.145 mmol) in EtOH (1 mL) was added concentrated ammoniumhydroxide (4.00 mL) and ammonium chloride (just enough to saturate thereaction) at room temperature. The reaction was heated to 100° C.overnight before the desired product was extracted using CH₂Cl₂(repeated 4 times). The organic layers were combined, dried over Na₂SO₄and concentrated to dryness. The residue was purified by flashchromatography (hexane/EtOAc 6:4 to 0:10) to give the title compound asa tan solid (0.008 g). LC/MS m/z 325 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.43 (td, J=2.10, 8.70 Hz, 2H), 7.37 (td, J=2.10, 8.70 Hz, 2H), 7.24 (d,J=8.72 Hz, 1H), 6.77 (br. s, 2H), 6.38 (d, J=8.72 Hz, 1H), 4.61 (s, 2H),2.56 (s, 3H).

5-(4-Chlorophenyl)-10-methyl-1H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2(7H)-one(Compound 220)

To a solution of5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine(0.050 g, 0.147 mmol) in AcOH (1 mL) was added concentrated 48%hydrobromic acid (1 mL) at room temperature. The reaction was heated to100° C. for 2 h before it was diluted with water, and the desiredproduct was extracted with a mixture CH₂Cl₂/trifluoroethanol (19:1)(repeated 4 times). The organic layers were combined, dried over Na₂SO₄and concentrated to dryness. The residue was purified by flashchromatography (hexane/EtOAc 7:3 to 0:10) to give the title compound asa white solid (0.019 g). LC/MS m/z 326 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ 11.79 (br. s, 1H), 7.51-7.41 (m, 4H), 7.36 (br. s, 1H), 6.41 (br. s,1H), 4.53 (br. s, 2H), 2.55 (s, 3H).

Example 40 Synthesis of8-Chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 240) and Related Compounds

3-Bromo-6-chloro-N-methoxy-N-methylpicolinamide

To a solution of 3-bromo-6-chloropicolinic acid (4.516 g, 19.10 mmol),N,0-dimethylhydroxylamine hydrochloride (3.73 g, 38.2 mmol), pyridine(4.63 mL, 57.3 mmol) in CH₂Cl₂ (40 mL) at 0° C. was added—N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (4.39 g, 22.92 mmol). After 1 h at 0° C., a saturatedaqueous solution of ammonium chloride was added and the product wasextracted with MTBE/EtOAc (4:1) (repeated 4 times). The organic layerswere combined, dried over Na₂SO₄ and concentrated to dryness. Theproduct was carried out without purification in the next step. LC/MS m/z281 [M+H]⁺.

(3-Bromo-6-chloropyridin-2-yl)(4-chlorophenyl)methanone

To a solution of 3-bromo-6-chloro-N-methoxy-N-methylpicolinamide (5.34g, 19.1 mmol) in anhydrous THF (38 mL) at 0° C. was slowly added asolution of (4-chlorophenyl)magnesium bromide (1M in Et₂O) (76 mL, 76mmol). After 3 h at 0° C., a saturated aqueous solution of ammoniumchloride was added and the product was extracted with MTBE (repeated 4times). The organic layers were combined, dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by flashchromatography (hexane/EtOAc 10:0 to 8:2) to give the title compound asa white solid (5.98 g). LC/MS m/z 332 [M+H]⁺.

8-Chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine

(Compound 240).

A sequence of reactions similar to the one used to prepare6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin(Compound 169) was followed, except that(3-bromo-6-chloropyridin-2-yl)(4-chlorophenyl) methanone as startingmaterial instead of the(4-chlorophenyl)(2-fluoro-4-iodopyridin-3-yl)methanone intermediate. Forthe Suzuki coupling reaction, a trifluoroborate salt was used instead ofthe boronic ester. LC/MS m/z 344 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ8.18 (d, J=8.72 Hz, 1H), 7.40 (s, 4H), 7.17 (d, J=8.72 Hz, 1H), 4.70(br. s, 2H), 2.50 (s, 3H).

6-(4-Chlorophenyl)-8-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 242)

A procedure similar to6-(4-Chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine(Compound 170) was followed, except that8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 240) was used as starting material instead of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine.LC/MS m/z 340 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (d, J=8.31 Hz,1H), 7.83 (d, J=8.31 Hz, 1H), 7.43 (td, J=2.30, 8.70 Hz, 2H), 7.35 (td,J=2.30, 8.70 Hz, 2H), 4.79 (br. s, 2H), 3.34 (s, 3H), 2.53 (s, 3H).

6-(4-Chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8-amine(Compound 241)

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine(Compound 173) was followed, except that8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 240) was used as starting material instead of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine.LC/MS m/z 339 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J=8.72 Hz,1H), 7.41 (td, J=2.10, 8.50 Hz, 2H), 7.36 (td, J=2.10, 8.50 Hz, 2H),6.96 (q, J=4.50 Hz, 1H), 6.77 (d, J=8.93 Hz, 1H), 4.61 (br. s, 2H), 2.62(d, J=4.78 Hz, 3H), 2.46 (s, 3H).

6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8-amine(Compound 257)

A procedure similar to5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine(Compound 228) was followed, except that8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 240) was used as starting material instead of2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine.LC/MS m/z 325 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, J=8.72 Hz,1H), 7.38 (td, J=2.10, 8.70 Hz, 2H), 7.33 (td, J=1.90, 8.70 Hz, 2H),6.76 (d, J=8.7 Hz, 1H), 6.39 (s, 2H), 4.60 (br. s, 2H), 2.46 (s, 3H).

6-(4-Chlorophenyl)-1-methyl-8-(pyrrolidin-1-yl)-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 247)

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8-amine(Compound 241) was followed, except that pyrrolidine was used instead ofmethylamine (33% in EtOH). LC/MS m/z 379 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 7.92 (d, J=8.93 Hz, 1H), 7.43 (td, J=2.20, 8.70 Hz, 2H), 7.36(td, J=2.20, 8.70 Hz, 2H), 6.79 (d, J=8.93 Hz, 1H), 4.62 (br. s, 2H),3.30-3.25 (m, 4H), 2.47 (s, 3H), 1.96-1.83 (m, 4H).

6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8(7H)-one(Compound 243)

A procedure similar to5-(4-chlorophenyl)-10-methyl-1H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2(7H)-onewas followed, except that6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepinewas used as starting material instead of5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine.LC/MS m/z 326 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.27 (br. s, 1H),8.01 (br. s, 1H), 7.50-7.31 (m, 4H), 6.85 (br. s, 1H), 4.66 (br. s, 2H),2.48 (s, 3H).

6-(4-Chlorophenyl)-1,7-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8(7H)-one(Compound 246)

A procedure similar to6-(4-chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-onewas followed, except that6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8(7H)-onewas used as starting material instead of6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one.LC/MS m/z 340 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J=9.56 Hz,1H), 7.48 (d, J=8.93 Hz, 2H), 7.35 (d, J=8.52 Hz, 2H), 6.82 (d, J=9.35Hz, 1H), 5.32 (d, J=12.46 Hz, 1H), 4.15 (d, J=12.7 Hz, 1H), 2.95 (s,3H), 2.50 (s, 3H).

8-Chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepine(Compound 256)

A sequence similar to8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine(Compound 240) was followed, except that 5-bromo-2-chloroisonicotinicacid was used as commercially available starting material instead of3-bromo-6-chloropicolinic acid. LC/MS m/z 344 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.93 (d, J=0.80 Hz, 1H), 7.49 (td, J=2.10, 8.70 Hz, 2H),7.46-7.42 (m, 3H), 4.77 (br. s, 2H), 2.57 (s, 3H).

6-(4-Chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepin-8-amine(Compound 258)

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-aminewas followed, except that8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepinewas used as starting material instead of6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine.LC/MS m/z 339 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H),7.49-7.41 (m, 4H), 6.84 (q, J=5.00 Hz, 1H), 6.33 (s, 1H), 4.67 (br. s,2H), 2.79 (d, J=4.78 Hz, 3H), 2.48 (s, 3H).

6-(4-Chlorophenyl)-1-methyl-8-(pyrrolidin-1-yl)-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepine(Compound 255)

A procedure similar to6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepin-8-aminewas followed, except that pyrrolidine was used instead of methylamine(33% in EtOH). LC/MS m/z 379 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.56(d, J=0.62 Hz, 1H), 7.48 (ddd, J=1.70, 2.50, 8.20 Hz, 2H), 7.44 (ddd,J=1.70, 2.50, 8.20 Hz, 2H), 6.23 (d, J=0.62 Hz, 1H), 4.66 (br. s, 2H),3.36-3.32 (m, 4H), 2.49 (s, 3H), 1.98-1.83 (m, 4H).

6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepin-8(9H)-one(Compound 266)

A procedure similar to5-(4-chlorophenyl)-10-methyl-1H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2(7H)-onewas followed, except that6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepine(prepared from8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepinein a similar fashion to6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine)was used as starting material instead of5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine.LC/MS m/z 326 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (br. s, 1H),7.92 (br. s, 1H), 7.48 (s, 4H), 6.25 (br. s, 1H), 4.78 (br. s, 2H), 2.43(s, 3H).

2-((4S)-7-Amino-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetamide(Compound 222)

A procedure similar to5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-aminewas followed, except that a solution of2-((4S)-6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-4-yl)acetamidein DMSO was used instead of a solution of2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepinein EtOH. LC/MS m/z 382 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d,J=5.19 Hz, 1H), 7.67 (br. s, 1H), 7.38 (td, J=2.30, 8.70 Hz, 2H), 7.33(td, J=2.30, 8.70 Hz, 2H), 7.04 (br. s, 1H), 6.95 (d, J=5.19 Hz, 1H),5.89 (br. s, 2H), 4.40 (dd, J=6.54, 8.00 Hz, 1H), 3.27 (dd, J=8.00 Hz,15.60, 1H), 3.11 (dd, J=6.65, 15.58 Hz, 1H), 2.49 (s, 3H).

Example 41 Synthesis of Compounds 232 and 244

Scheme 10 depicts the synthesis of the title compounds.

Methyl2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate

To a re-sealable vial containing a solution of tert-butyl2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(1.04 g, 3.17 mmol) in MeOH (10 mL) was added hydrochloric acid (0.792mL, 3.17 mmol, 4 M in 1,4-dioxane). After complete addition of reagentsthe reaction mixture was allowed to age until complete consumption ofthe carboxylic acid was detected by LC-MS. After ˜24 h, the reactionmixture was cooled to room temperature and concentrated in vacuo to giveyellow solids. The solids were purified on Biotage system (gradientelution 5% EtOAc:1% i-PrOH: 94% Hexanes to 80% EtOAc:1% i-PrOH:19%Hexanes) to give the titled product methyl2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.500 g, 1.747 mmol, 55.1% yield) as white crystalline solids. LC/MSm/z 287 [M+H]⁺.

Methyl2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate

To a solution of methyl2-((4S)-1-methyl-6-oxo-5,6-dihydro-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.4754 g, 1.661 mmol) in CH₂Cl₂ (4 mL) was added phosphoruspentachloride (0.432 g, 2.075 mmol). The reaction mixture was stirred atroom temperature for 1 h. To the mixture was added aqueous 10% Na₂CO₃and stirred vigorously for 15 min. The aqueous layer was extracted withCH₂Cl₂ (3×). The combined organic extracts were dried over Na₂SO₄ andconcentrated to give yellow foam after drying. The foam was filteredover a plug of silica and eluted with 20% EtOAc:80% Hexanes. The productmethyl2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.4701 g, 1.543 mmol, 93% yield) was obtained as a white foam. LC/MSm/z 305 [M+H]⁺.

Methyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate

To a 100 mL round bottom flask containing methyl2-((4S)-6-chloro-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.4701 g, 1.543 mmol) was added Pd(PPh₃)₄ (0.095 g, 0.082 mmol) and4-chlorophenylboronic acid (0.393 g, 2.51 mmol). The flask was evacuatedand purged with N₂ (g) (3×), followed by addition of toluene (10 mL) andanother cycle of evacuation and purging with N₂ (g). To theheterogeneous mixture was added aqueous sodium carbonate (2.4 mL, 4.80mmol, 2 M) in one portion and the flask was heated to 80° C. After ˜30min, the reaction mixture was cooled to room temperature and dilutedwith water. The aqueous layer was extracted with EtOAc (3×), dried overNa₂SO₄, and concentrated to give a dark orange oil. The oil was purifiedon Biotage system (5% EtOAc:95% Hexanes to 35% EtOAc:65% Hexanes, thenisocratic 35% EtOAc:65% Hexanes). The product methyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.444 g, 1.166 mmol, 76% yield) was obtained as yellow foam afterdrying. LC/MS m/z 381 [M+H]⁺.

3-((4S)-6-(4-Chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropane-2,2-diol

A vial containing methyl2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate(0.110 g, 0.289 mmol) and CsF (0.028 g, 0.184 mmol, dried under vacuumat 140° C. for 24 h) was evacuated and purged with N₂ (g), followed byaddition of DME (1 mL). The heterogeneous mixture was cooled to 0° C.and trimethyl(trifluoromethyl)silane (0.085 mL, 0.578 mmol) was added ina dropwise manner. The reaction mixture was carefully monitored by LC-MSand TLC for complete consumption of starting methyl ester. After 30 min,aqueous 1 N HCl (1 mL) was added to the mixture. Vigorous evolution ofgas was observed! The biphasic mixture was warmed to room temperatureand diluted with MTBE. The aqueous layer was extracted with MTBE (2×),the combined organic extracts were washed with water, and dried overNa₂SO₄, and concentrated to give the(4S)-6-(4-chlorophenyl)-1-methyl-4-(3,3,3-trifluoro-2-methoxy-2-((trimethylsilyl)oxy)propyl)-4H-benzo[c]isoxazolo[4,5-e]azepineanas an orange-yellow oil. LC/MS m/z 523 [M+H]⁺.

To a cooled (0° C.) solution of crude(4S)-6-(4-chlorophenyl)-1-methyl-4-(3,3,3-trifluoro-2-methoxy-2-((trimethylsilyl)oxy)propyl)-4H-benzo[c]isoxazolo[4,5-e]azepinein MeOH (3 mL) was added CsF (0.048 g, 0.316 mmol). The reaction wasmaintained at 0° C. for 30-60 min or until complete conversion ofstarting material to the desired ketone/di-hydrate was observed. Thereaction mixture was diluted with MTBE and aqueous 1 N HCl was addeduntil a phase cut was observed. The aqueous phase was extracted withMTBE (3×), the combined organic phases were washed with water, driedover Na₂SO₄, and concentrated to give the desired product as an orangeoil. The product3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropane-2,2-diol(0.121 g, 0.277 mmol, 96% yield) was used without further purification.LC/MS m/z 437 [M+H]⁺.

Mixture of(2S)-3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-amineand(2R)-3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-amine(Compound 232)

To a re-sealable vial containing a solution of3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropane-2,2-diol(110 mg, 0.252 mmol) in toluene (1 mL) was added p-toluenesulfonic acidmonohydrate (25 mg, 0.131 mmol) and benzylamine (50 μl, 0.458 mmol). Thevial was sealed and heated to 110° C. for 1-2 h or until TLC (1% TEA:30%EtOAc:69% Hex) analysis indicated complete conversion to imine. Thereaction mixture was subsequently cooled to room temperature,triethylamine (110 μl, 0.789 mmol) was introduced, and the reaction wasagain heated to 110° C. for 24 h. After 24 h, the reaction mixture wascooled to room temperature. The solution was diluted with MTBE andwater. The aqueous layer was extracted with MTBE (3×) and the combinedorganic extracts were washed with additional water (1×). The combinedorganic layers were concentrated to yield an orange oil. To the oil wassubsequently introduced CSA (37.5 mg, 0.161 mmol) and MeOH (5 mL) andthe mixture was stirred for 3 h. The hydrolysis of the imine wasfollowed by LC-MS and TLC. After complete hydrolysis (˜3 h), thereaction mixture was concentrated to give a yellow oil. The oil waspurified on Biotage system (gradient elution 5% EtOAc:95% Hexanes to 40%EtOAc:60% Hexanes) to give a 1:1 inseparable mixture of the titledproduct(s)(2S)-3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-amineand(2R)-3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-amine(43 mg, 0.102 mmol, 40.7% yield) as white solids. LC/MS m/z 420 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 7.86-7.80 (m, 2H), 7.75-7.69 (m, 2H), 7.44(s, 12H), 4.34-4.18 (m, 2H), 3.82-3.63 (m, 1H), 3.58-3.41 (m, 1H), 2.53(s, 3H), 2.52 (s, 3H), 2.15-2.08 (m, 2H), 2.06-2.00 (m, 2H).

Mixture ofN-((2S)-3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-yl)acetamideandN-((2R)-3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-yl)acetamide(Compound 244)

To a solution of3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-amine(11 mg, 0.026 mmol) in CH₂Cl₂ (0.5 mL) was added DMAP (3.20 mg, 0.026mmol), triethylamine (11 μl, 0.079 mmol), and acetic anhydride (2.72 μl,0.029 mmol). The reaction mixture was stirred until the completeconsumption of amine and formation of product was detected by LC-MS andTLC. The reaction mixture was concentrated in vacuo to give a thickpaste. The paste was purified on Biotage (5% EtOAc:Hexanes to 40%EtOAc:Hexanes) The productN-(3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropan-2-yl)acetamide(10 mg, 0.022 mmol, 83% yield) was isolated as white solids. LC/MS m/z462 [M+H]⁺; 1H NMR (400 MHz, Acetone-d₆) δ 7.87-7.80 (m, 2H), 7.75-7.68(m, 2H), 7.51-7.35 (m, 12H), 5.46 (br. s, 1H), 5.16-5.00 (m, 1H), 4.16(br. s, 1H), 4.05 (br. s, 1H), 3.01-2.83 (m, 2H), 2.68 (ddd, J=7.02,9.80, 14.19 Hz, 1H), 2.55 (s, 3H), 2.54 (s, 3H), 2.51-2.39 (m, 1H), 1.90(s, 3H), 1.83 (s, 3H).

Example 42 Synthesis of Compounds 250 and 251

Scheme 11 depicts the steps involved in the synthesis of the titlecompounds.

Ethyl 2-(3-methylisoxazol-5-yl)acetate

To a solution of 2-(3-methylisoxazol-5-yl)acetic acid (7.28 g, 51.6mmol) in EtOH (200 mL, 3425 mmol) was added concentrated H₂SO₄ (0.30 mL,5.63 mmol) at room temperature. After 48 h, the reaction mixture wasconcentrated in vacuo to give a dark brown oil. The crude ester wasfiltered over a plug of silica (50 g) and the product was eluted with40% Et₂O:60% Hexanes (400 mL). The filtrate was subsequentlyconcentrated to give the product ethyl 2-(3-methylisoxazol-5-yl)acetate(8.50 g, 50.2 mmol, 97% yield) as a clear oil. LC/MS m/z 170 [M+H]⁺.

Ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate

To a solution of ethyl 2-(3-methylisoxazol-5-yl)acetate (8.22 g, 48.6mmol) in toluene (85 mL) was sequentially added n-tetrabutylammoniumbromide (1.67 g, 5.18 mmol), 1,2-dibromoethane (7.0 mL, 81 mmol), andNaOH (30 mL, 582 mmol, ˜19.4 M). The reaction mixture was vigorouslystirred at room temperature. After 1 h, the reaction mixture was cooledto 0° C. and diluted with water (50 mL). The aqueous phase was extractedwith MTBE (3×). The combined organic phases were washed 1 N HCl, water(2×), dried over Na₂SO₄, and concentrated to give the product ethyl1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (9.49 g, 48.6 mmol,100% yield) as a clear oil. LC/MS m/z 196 [M+H]⁺.

Ethyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate

To a solution of ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate(9.49 g, 48.6 mmol) in anhydrous DMF (50 mL) was addedN-bromosuccinimide (10.31 g, 57.9 mmol). The reaction mixture wasstirred at room temperature for 24 h. To the orange mixture was addedwater and the aqueous layer was extracted with MTBE (3×). The combinedorganic layers were washed with aqueous 10% sodium thiosulfate, water(2×) and dried to provide the product ethyl1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate (12.5 g, 45.6mmol, 94% yield) as a light yellow oil. The product was used directly inthe subsequent reaction without further purification. LC/MS m/z 274[M+H]⁺.

1-(4-Bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylic acid

To a solution of ethyl1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate (11.8 g, 43.0mmol) in THF (60 mL) was added aqueous NaOH (86 mL, 86 mmol, 1 M). Thedark brown bi-phasic reaction mixture was vigorously stirred and heatedto 45° C. until consumption of SM (3-4 h) was detected by LC-MS and TLCanalysis. After 4 h, the homogeneous mixture was cooled to roomtemperature and diluted with hexanes. The organic phase was separatedand the aqueous phase (pH ˜14) was acidified with aqueous 1 N HCl (pH 1)(˜100 mL). The product crystallizes upon acidification of the aqueouslayer. After vigorously stirring for 30 min, the solids were filtered,washed with cold (0° C.) water (3×50 mL), and dried to give whitecrystals. The product1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylic acid (10.0 g,40.6 mmol, 94% yield) was isolated as white crystals. LC/MS m/z 246[M+H]⁺.

Tert-Butyl (1-(4-bromo-3-methylisoxazol-5-yl)cyclopropyl)carbamate

To a suspension of1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylic acid (1.60 g,6.50 mmol) and powdered 4 Å molecular sieves (pre-dried-0.767 g, 48% wt)in toluene (15 mL) was sequentially added N,N-diisopropylethylamine(1.50 mL, 8.59 mmol), diphenyl phosphorazidate (1.576 mL, 7.05 mmol),and tert-butanol (16.80 mL, 176 mmol). The reaction vessel was fittedwith a reflux condenser and the mixture was heated to 100° C. for 1 h.After 1 h, the reaction mixture was cooled to room temperature andfiltered over a plug of Celite. The filter cake was washed with EtOAc(3×), and the filtrate was concentrated to give a brown oil. The oil waspurified on Biotage system (5% EtOAc:95% Hexanes to 20% EtOAc:80%Hexanes). The product tert-butyl1-(4-bromo-3-methylisoxazol-5-yl)cyclopropylcarbamate (1.55 g, 4.89mmol, 75% yield) was isolated as white crystals after concentration.LC/MS m/z 317 [M+H]⁺.

Tert-Butyl(1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropyl)carbamate

To a 50 mL round bottom flask containing tert-butyl1-(4-bromo-3-methylisoxazol-5-yl)cyclopropylcarbamate (0.219 g, 0.621mmol) was added dichlorobis(acetonitrile)palladium(II) (0.0025 g, 9.64μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.0134 g,0.033 mmol), followed by anhydrous 1,4-dioxane (0.40 mL). The reactionvessel was evacuated and purged with N₂ (g) (3×). To the flask was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.153 mL, 1.056 mmol) andtriethylamine (0.294 mL, 2.113 mmol) sequentially. The reaction vesselwas evacuated and purged with N₂ (g) again, then heated to 100° C. Thereaction mixture became heterogeneous and was judged complete within 1 hby LC-MS. The heterogeneous mixture was cooled to room temperature,dilute with EtOAc and the mixture was filtered over a plug of Celite.The filter cake was rinsed with EtOAc (3×) and the filtrate wasconcentrated to give a yellow oil, that crystallized upon standing undervacuum. The product tert-butyl1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate(0.226 g, 0.620 mmol, 100% yield) was used without further purification.LC/MS m/z 365 [M+H]⁺.

Methyl2-(5-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate

A re-sealable vial containing methyl 2-bromo-5-chlorobenzoate (0.205 g,0.822 mmol), Pd(Ph₃P)₄ (0.042 g, 0.036 mmol), and anhydrous potassiumphosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged withN₂ (g) (3×). To the solids was added a solution of tert-butyl1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate(0.236 g, 0.648 mmol) in MeOH (2×1 mL, 2 mL total) and 1,4-Dioxane (2×1mL, 2 mL total). The suspension was evacuated and purged with N₂ (g)(3×), the vial was sealed, and the contents heated to 80° C. LC-MSanalysis indicated complete conversion to desired product with in 4 h.After 4 h, the reaction mixture was cooled to room temperature andfiltered over Celite. The filter cake was washed with MeOH (3×) and thefiltrate was concentrated to give a brown oil. The oil was purified onBiotage system (5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, thenisocratic 30% EtOAc:70% Hexanes). The product methyl2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate(0.226 g, 0.555 mmol, 86% yield) was isolated as a clear oil. LC/MS m/z407 [M+H]⁺.

8-Chloro-1-methylspiro[benzo[c]isoxazolo[4,5-e]azepine-4,1′-cyclopropan]-6(5H)-one

To a solution of methyl2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate(131 mg, 0.322 mmol) in MeOH (2 mL) was added anhydrous HCl (1.00 mL,4.00 mmol, 4 M in 1,4-dioxane). The reaction mixture was stirred at roomtemperature for 6 h, at which point LC-MS analysis indicated completeconsumption of N-Boc carbamate and formation of desired product. Thereaction mixture was concentrated in vacuo and excess HCl wasazeotropically removed with MeOH (1×1 mL), toluene (1×1 mL), and THF(1×1 mL). The resultant yellow oil was dried for 10 min LC/MS m/z 307[M+H]⁺.

To a cooled (−40° C.) suspension of crude ammonium hydrochloride salt(˜100 mg) in THF (1.5 mL) was added isopropylmagnesium bromide (0.400mL, 1.160 mmol) in a dropwise manner. After complete addition, thereaction mixture was allowed to warm to room temperature and stirred foran additional 15 min. To the reaction mixture was added aqueous 1 N HCl(until pH ˜1 was obtained for the aqueous layer). The aqueous phase wasextracted with EtOAc and the combined organic phase was washed withwater, dried over Na₂SO₄ and concentrated to give the product8-chloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropan]-6(5H)-one(0.0631 g, 0.230 mmol, 71.3% yield over 2-steps) as light yellow solids.The crude product was sufficiently pure by LC-MS analysis and usedwithout further purification. LC/MS m/z 275 [M+H]⁺.

6,8-Dichloro-1-methylspiro[benzo[c]isoxazolo[4,5-e]azepine-4,1′-cyclopropane]

To a vial containing8-chloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropan]-6(5H)-one(0.0631 g, 0.230 mmol) was added CH₂Cl₂ (1 mL). The reaction mixture washeterogeneous and to aid in solubility CHCl₃ (0.5 mL) was added. To thehomogeneous mixture was added phosphorous pentachloride (0.092 g, 0.442mmol) in one portion at room temperature. The reaction mixtureeventually turned heterogeneous again (˜<10 min) and LC-MS analysisafter ˜30 min indicated complete consumption of starting material andformation of desired product. The mixture was diluted with EtOAc andaqueous 10% Na₂CO₃ (2.8 mL). After initial effervescence, the mixturewas stirred for an additional 5-10 min, and the aqueous layer wasextracted with EtOAc (3×). The combine organic extracts were washed withwater, brine, dried over Na₂SO₄ and concentrated to give yellow solids.The solids were filtered over a plug of silica and eluted with 30%EtOAc:70% Hexanes. The product6,8-dichloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane](61.8 mg, 0.211 mmol, 92% yield) was obtained as off-white solids. LC/MSm/z 293 [M+H]⁺.

8-Chloro-6-(4-fluorophenyl)-1-methylspiro[benzo[c]isoxazolo[4,5-e]azepine-4,1′-cyclopropane](Compound 250)

To a solution of6,8-dichloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane](61.9 mg, 0.211 mmol) in toluene (22 mL) was added 4-fluorophenylboronicacid (37 mg, 0.264 mmol) and Pd(Ph₃P)₄ (11.22 mg, 9.71 μmol). Thereaction was evacuated and purged with N₂ (g) (3×), followed by additionof aqueous Na₂CO₃ (211 μl, 0.422 mmol, 2 M). The reaction was heated to82° C. for 15 min at which time LC-MS analysis indicated completeconversion to desired product. The reaction mixture was cooled to roomtemperature and diluted with water. The aqueous layer was extracted withEtOAc (3×) and the combined organic extracts were dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified on Biotage system(5% EtOAc:95% Hexanes to 10% EtOAc:90% Hexanes). The product8-chloro-6-(4-fluorophenyl)-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane](62 mg, 0.176 mmol, 83% yield) was obtained as a white crystals. LC/MSm/z 353 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.77 (m, 1H), 7.75-7.71(m, 1H), 7.45-7.38 (m, 2H), 7.19-7.26 (m, 3H), 2.52 (s, 3H), 1.29 (s,4H).

5-(6-(4-Fluorophenyl)-1-methylspiro[benzo[c]isoxazolo[4,5-e]azepine-4,1′-cyclopropan]-8-yl)pyridin-2-amine(Compound 251)

To a 25 mL round bottom flask containing8-chloro-6-(4-fluorophenyl)-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane](57mg, 0.162 mmol) was added Pd₂(dba)₃ (9.1 mg, 9.94 μmol),tri-tert-butylphosphonium tetrafluoroborate (6.5 mg, 0.022 mmol),potassium phosphate (77 mg, 0.363 mmol), and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (56 mg,0.254 mmol). The flask was evacuated and purged with N₂ (g) (3×),followed by addition of 1,4-dioxane (1 mL) and water (0.05 mL). Theflask was evacuated and purged with N₂ (g) (3×) and the reaction mixturewas heated to 100° C. After 3 h, ˜50% conversion of starting materialwas observed by LC-MS analysis. The reaction mixture was cooled to roomtemperature and additional Pd₂(dba)₃ (9.1 mg, 9.94 μmol),tri-tert-butylphosphonium tetrafluoroborate (6.5 mg, 0.022 mmol),potassium phosphate (77 mg, 0.363 mmol), and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (56 mg,0.254 mmol) were introduced. The mixture was subsequently heated againfor an additional 24 h. LC-MS analysis after 24 h, indicated ˜80%conversion to desired product. The reaction mixture was cooled andfiltered over a pad of Celite. The filter cake was washed with EtOAc(3×) and the filtrate was concentrated to give a dark brown oil. The oilwas purified on Biotage system (25% EtOAc:75% Hexanes to 70% EtOAc:30%Hexanes, then isocratic 70% EtOAc:30% Hexanes). The product wasconcentrated to give gummy yellow solid that was contaminated with2-amino-pyridine. The solid was triturated with IPA (1 mL) and Et₂O (1mL) and filtered. The solids were washed with ether (1 mL) and filtered.The amino pyridine (yellow color) was cleanly removed in the rinses andthe product5-(6-(4-fluorophenyl)-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane]-8-yl)pyridin-2-amine(0.032 g, 0.078 mmol, 48.3% yield) was isolated as white-solids. LC/MSm/z 411 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (d, J=2.49 Hz, 1H),7.86 (dd, J=1.97, 8.21 Hz, 1H), 7.79 (s, 1H), 7.59 (dd, J=2.60, 8.62 Hz,1H), 7.49-7.42 (m, 2H), 7.37 (d, J=1.87 Hz, 1H), 7.24-7.15 (m, 2H), 6.49(dd, J=0.62, 8.72 Hz, 1H), 6.14 (s, 2H), 2.54 (s, 3H), 1.28 (d, J=6.02Hz, 4H).

Example 42A Synthesis of Compound 265

4-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide

A mixture of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (2.04 g, 10mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (3.21 g, 10 mmol), N,O-dimethylhydroxylamine (1.22 g,20 mmol) in N,N-Diisopropylethylamine (5 mL) and N,N-Dimethylformamide(20 mL) was stirred for 12 h at room temperature. The mixture wasconcentrated in vacuum, and the residue was purified by flashchromatography eluting with petroleum ether/ethyl acetate=5:1 to givethe titled product as a colorless oil (2.4 g, 97%). LC/MS m/z 247[M+H]⁺.

(4-bromo-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)methanone

To a solution of compound4-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide (1.0 g, 4 mmol)in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere was added(4-chlorophenyl)magnesium bromide (8 mL) in tetrahydrofuran (1 M) at 0°C., The resulting mixture was stirred for 2 h at room temperature. Thereaction was quenched by saturated solution of ammonium chloride, anddichloromethane (100 mL) was added, the separated organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuum. Theresidue was purified by flash chromatography eluting with petroleumether/ethyl acetate=5:1 to give the titled product as a white solid (1.0g, 84%). LC/MS m/z 298 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J=9Hz, 2H), 7.53 (s, 1H), 7.43 (d, J=9 Hz, 2H), 3.99 (s, 3H).

(4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methylacetate

A solution of(4-bromo-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)methanone(4-bromo-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)methanone (0.5 g, 1.7mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (62mg, 0.085 mmol), K₂CO₃ (0.94 g, 6.8 mmol),(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methylacetate (0.96 g, 3.4 mmol) in water (2 mL) and 1,4-dioxane (10 mL) washeated at 90° C., and stirred for 4 hours. After cooling to roomtemperature, DCM (100 mL) was added and the layers separated. Theseparated organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by flash chromatography elutingwith petroleum ether/ethyl acetate=5:1 to give the titled product as ayellow oil (0.3 g, 47%). LC/MS m/z 373 [M+H]⁺.

(4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone

To a solution of(4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methylacetate (0.3 g, 0.8 mmol) in THF (10 mL), was added NaOH solution (5 mL,1 N in water). The mixture was stirred for 2 hours at 55° C. Aftercooling to room temperature, DCM (50 mL) was added and the layersseparated. The separated organic layer was dried over anhydrous sodiumsulfate and concentrated to afford the titled product as a yellow oil(0.2 g, 75% yield). LC/MS m/z 331 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.13(d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 3H), 4.62 (s, 2H), 4.07 (s, 3H), 2.15(s, 3H).

(4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methylmethanesulfonate

To a solution of(4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone(0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) andmethane sulfonyl chloride (0.05 mL) at room temperature. The mixture wasstirred for 2 h at room temperature. DCM (50 mL) and saturated sodiumbicarbonate solution (20 mL) were added. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated to afford thetitled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]⁺.

(4-(5-(azidomethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)methanone

A mixture of(4-(3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl)-3-methylisoxazol-5-yl)methylmethanesulfonate (35 mg, 0.09 mmol), sodium azide (12 mg, 0.18 mmol) inN,N-dimethylformamide (10 mL) was heated to 80° C. and stirred for 10 h.After cooling to room temperature, the mixture was concentrated, and theresidue was purified by flash chromatography eluting with petroleumether/ethyl acetate=1:3 to give the titled product as a colorless oil(30 mg, 94%). LC/MS: m/z 356 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d,J=9 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J=9 Hz, 2H), 4.37 (s, 2H), 4.09 (s,3H), 2.19 (s, 3H).

6-(4-chlorophenyl)-1,8-dimethyl-4,8-dihydroisoxazolo[5,4-c]pyrazolo[4,3-e]azepine(Compound 265)

To a solution of(4-(5-(azidomethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)methanone(0.03 g, 0.08 mmol) in anhydrous THF (10 mL), was addedtriphenylphosphine (32 mg, 0.12 mmol) at room temperature. The mixturewas stirred for 12 h at room temperature. The mixture was concentratedand the residue was purified by flash chromatography eluting with(petroleum ether/ethyl acetate=1:3) to afford the title compound as awhite solid (15 mg, 60% yield). LC/MS: m/z 312 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃) δ 7.62 (d, J=9 Hz, 3H), 7.36 (d, J=9 Hz, 2H), 4.87 (s, 2H), 4.08(s, 3H), 2.45 (s, 3H).

Example 43 Synthesis of Compound 209

(2R)-tert-butyl2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)propanoate

To a round bottomed flask was added THF (50 mL) and diisopropylamine(1.29 mL, 9.10 mmol) before the solution was cooled to 0° C. To thissolution was added n-BuLi (3.62 mL, 8.69 mmol) and the reaction wasstirred at 0° C. for 10 min before cooling to −78° C. and addition oftert-butyl2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)acetate(1.5 g, 4.14 mmol), a form of intermediate 17, prepared according toExample 14. The solution was stirred at −78° C. for 1 h before additionof iodomethane (0.285 mL, 4.55 mmol) and warming to room temperatureovernight. The reaction was quenched with saturated aqueous NH₄Clsolution and then diluted with water and brine. The aqueous layer wasextracted with EtOAc and the combined organic layer was dried overNa₂SO₄, filtered, and concentrated. The crude residue was purified viaBiotage (MTBE/hexanes) to afford the titled product (0.259 g, 0.688mmol).

(2R)-2-((6S)-4-(4-cyanophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)propanamide(Compound 209)

This compound was synthesized from. (2R)-tert-butyl2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)propanoatefollowing general procedures H, L to afford the titled compound (0.099g, 0.245 mmol).

Example 44 Additional Compounds of the Invention

Additional compounds of the invention made by the various schemesdisclosed above are set forth in Table 13 below, including theidentification of the final steps utilized in their syntheses.

TABLE 13 Other Compounds of the Invention Compound Final No. StructurePhysical Data steps 200

LC/MS m/z 435 [M + H]⁺; ¹H NMR (400 MHz ,DMSO-d₆) δ 7.94-7.85 (m, 1H),7.83-7.73 (m, 4H), 7.53 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 2.1 Hz, 1H),4.38 (br. s, 2H), 3.34 (br. s, 1H), 2.51 (s, 2H). H, L (amide formationstep was eliminated) 209

LC/MS m/z 405 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (d, J = 8.47Hz, 2H), 7.65 (br. s, 1H), 7.40 (d, J = 8.01 Hz, 2H), 7.02 (br. s, 1H),3.88 (d, J = 10.30 Hz, 1H), 3.55 (dd, J = 6.98, 10.41 Hz, 1H), 2.45 (s,3H), 2.41 (s, 3H), 1.58 (s, 3H), 1.27 (d, J = 6.64 Hz, 3H). H, L 202

LC/MS m/z 449 [M + H]⁺; ¹H NMR (300 MHz, Acetone-d₆) δ 7.85-7.88 (m,1H), 7.74 (t, J = 9 Hz, 1H), 7.51-7.54 (m, 1H), 7.39-7.44 (m, 2H),7.24-7.27 (m, 2H), 7.18 (s, 1H), 6.43 (m, 1H), 4.5 (t, J = 6 Hz, 1H),3.37 (d, J = 3 Hz, 2H), 2.56 (s, 3H). H, L

Example 44A Biological Activity of Compounds 192-266

The activity of Compounds 192-266 in the BRD4 AlphaLisa Binding Assay(“Alphascreen”) (see Example 24), cMyc RNA quantification assay andCell-based IL-6 quantification assay are set forth in Table 14, below.In Table 14, n.t.=not tested, “+” represents a value under 0.50 μM; “++”a value between 0.50 μM and 1 μM; and “+++” a value greater than 1 μM.

TABLE 14 Activity of Compounds 192-266. Compound # Alpha screen IL6MYC-Raji MYC-MV411 192 + ++ ++ n.t. 193 ++ +++ n.t. n.t. 194 +++ +++n.t. n.t. 195 +++ +++ n.t. n.t. 196 +++ ++ +++ n.t. 197 + + + n.t.198 + + ++ n.t. 199 + + + n.t. 200 +++ +++ +++ n.t. 201 + + ++ n.t.202 + + + + 203 + + + + 204 + + ++ n.t. 205 + + +++ n.t. 206 + + + +208 + + + + 209 + + ++ + 210 + + ++ + 211 + + n.t. ++ 212 + + n.t. +213 + + n.t. + 214 + + n.t. + 215 +++ +++ n.t. +++ 216 + + n.t. +217 + + n.t. + 218 +++ +++ n.t. +++ 219 +++ +++ n.t. ++ 220 +++ +++ n.t.+++ 221 +++ +++ n.t. +++ 222 + + n.t. + 223 +++ +++ n.t. +++ 224 + +n.t. + 225 + + n.t. + 226 + + n.t. + 227 +++ +++ n.t. +++ 228 +++ +++n.t. +++ 229 +++ +++ n.t. +++ 230 + + n.t. ++ 231 + + n.t. + 232 +++ +++n.t. +++ 233 + ++ n.t. ++ 234 + ++ n.t. ++ 235 + + n.t. + 236 + + n.t. +237 + + n.t. + 238 +++ +++ n.t. +++ 239 + + n.t. + 240 +++ +++ n.t. +++241 + + n.t. + 242 ++ +++ n.t. +++ 243 ++ +++ n.t. +++ 244 +++ +++ n.t.+++ 245 + + n.t. + 246 ++ +++ n.t. +++ 247 + + n.t. ++ 248 + + n.t. +249 + + n.t. + 250 +++ +++ n.t. +++ 251 + + n.t. + 252 +++ +++ n.t. +++253 + + n.t. + 254 ++ +++ n.t. +++ 255 + + n.t. ++ 256 +++ +++ n.t. +++257 + ++ n.t. +++ 258 + n.t. n.t. n.t. 259 + n.t. n.t. n.t. 260 + n.t.n.t. n.t. 261 + + n.t. n.t. 262 + + n.t. n.t. 263 + + n.t. n.t. 264 ++++++ n.t. n.t. 265 +++ +++ n.t. n.t. 266 + + n.t. n.t.

Example 44B In-Vivo Inhibition of LPS-Induced IL-6 Production Protocol

Female Balb/C mice, 6 weeks old upon arrival at animal facility, andweighing 18-20 g/mouse were used for this assay. The mice are acclimatedin animal facility for 5-7 days prior experiment initiation. Mice wererandomly divided into experimental groups to include several doses oftest article, and vehicle and dexamethasone controls. Mice were fastedfrom 12 hours prior to study initiation (dosing), but allowed freeaccess to water. Mice were dosed following study group design by oralgavage 30 min prior to LPS stimulation. Dosing interval time was 1min/mouse.

Two hours after LPS challenge animals were anesthetized by CO₂inhalation, and blood was sampled via cardiac puncture into EDTA coatedtubes and placed on ice. Plasma was separated by centrifugation at 3000g at 4° C. for 15 min. The separated plasma was divided into aliquots(50 ul/aliquot) and stored at −80° C. until plasma IL-6 ELISA and druglevels were analyzed. Compound concentrations are also sampled fromsatellite groups 30 min after dosing (and hence at time of LPSstimulation).

ELISA were run by following standard protocols and ED₅₀ was calculatedbased on 50% inhibition compared to vehicle control. The results are setforth in Table 15. (“++” indicates an ED₅₀ of less than 10 mg/kg; “+”indicates and ED₅₀ of between 10 and 50 mg/kg.

TABLE 15 Compound # ED₅₀ (mg/kg) 110 ++ 128 ++ 129 ++ 132 ++ 144 ++148 + 165 +

Example 45 Myc RNA Quantification in Xenograft Model

Female NOD SCID mice (Harlan) were inoculated s.c. with 3×10⁶ Raji cellsper mouse resuspended in 10% Matrigel. Tumors were grown until theyreached a size of 200 mm³ to 400 mm³ as measured by caliper. Mice weretreated orally (5 mL/kg) with different doses of compounds prepared as a2 mg/mL suspension of Carboxy-methyl-cellulose. At the indicated timepoints after treatment, tumors were harvested. RNA was isolated by usingTRIzol extraction and processed for QuantiGene® Assay. ED₅₀s werecalculated based on 50% inhibition compared to vehicle control. Theresults are set forth in Table 16. (“++” indicates an ED₅₀ of less than20 mg/kg; “+” indicates and ED₅₀ of between 20 and 50 mg/kg.

TABLE 16 Compound # ED₅₀ (mg/kg) 110 + 129 + 132 ++ 144 ++ 114 +

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

1-7. (canceled)
 8. A method of treating a cancer selected fromadenocarcinoma, adenoid cystic carcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectalcancer, diffuse large B-cell lymphoma, esophageal cancer, follicularlymphoma, gastrointestinal cancer, glioblastoma multiforme, glioma,gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin'slymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer,laryngeal cancer, leukemia, lung cancer, liver cancer, small cell lungcancer, non-small cell lung cancer, mesothelioma, midline carcinoma,multiple myeloma, neuroblastoma, ocular cancer, optic nerve tumor, oralcancer, ovarian cancer, pituitary tumor, primary central nervous systemlymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renalcell carcinoma, rectal cancer, sarcoma, skin cancer, soft tissuesarcoma, spinal tumor, small intestine cancer, stomach cancer, T-celllymphoma, testicular cancer, thyroid cancer, throat cancer, urogenitalcancer, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms'tumor in a patient in need thereof, comprising administering to thepatient a compound of formula II-A:

or a pharmaceutically acceptable salt thereof, wherein: R₁ is H, alkyl,aralkyl, aryl, heteroaryl, halo, OR_(A), NR_(A)R_(B), S(O)_(q)R_(A),C(O)R_(A), C(O)OR_(A), OC(O)R_(A), or C(O)NR_(A)R_(B); each R_(A) isindependently optionally substituted alkyl, containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; each R_(B) isindependently optionally substituted alkyl, containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; Ring A is benzo; R^(C)is a 3-7 membered saturated, partially unsaturated or completelyunsaturated carbocyclic ring; a 3-7 membered aryl ring; or a 3-7membered saturated, partially unsaturated, or completely unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein R^(C) is optionally substitutedwith 1-5 independently selected R₄; R₂ and R₃ are each independently H,halogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl, —OR,—SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R, C(O)N(R′)(R″), —C(O)SR, or—(CH₂)_(p)R_(x); or R₂ and R₃ together with the atoms to which each isattached, forms an optionally substituted 3-7 membered saturated orpartially unsaturated spiro-fused ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each R_(x) isindependently halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted heteroaryl, optionally substitutedheterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R, —CO₂R,—C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″),—C(S)OR, —S(O)R, —SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),—N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″), —N(R′)N(R′)(R″),—N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″),—OC(O)R, —OC(O)N(R′)(R″); each R is independently hydrogen, C₁₋₆aliphatic, a 5-6 membered aryl ring, a 3-7 membered saturated, partiallyunsaturated, or completely unsaturated carbocyclic ring, a 7-12 memberedbicyclic saturated, partially unsaturated, or completely unsaturatedcarbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur, a3-7 membered saturated, partially unsaturated, or completely unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 7-12 membered bicyclic saturated,partially unsaturated, or completely unsaturated heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or a 7-12 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of which is optionally substituted; each R′ is independently —R,—C(O)R, —C(S)R, —CO₂R, —C(O)N(R)₂, —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂,or two R on the same nitrogen are taken together with their interveningatoms to form a 3-7 membered monocyclic saturated, partiallyunsaturated, or completely unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; a7-12 membered bicyclic saturated, partially unsaturated, or completelyunsaturated fused heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclicheteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of whichis optionally substituted; each R″ is independently —R, —C(O)R, —C(S)R,—CO₂R, —C(O)N(R)₂, —C(S)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, or two R on thesame nitrogen are taken together with their intervening atoms to form a3-7 membered monocyclic saturated, partially unsaturated, or completelyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclicsaturated, partially unsaturated, or completely unsaturated fusedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring;or a 7-12 membered bicyclic heteroaryl; each of which is optionallysubstituted; or R′ and R″, together with the atoms to which each isattached, can form a 3-7 membered monocyclic saturated, partiallyunsaturated, or completely unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; a7-12 membered bicyclic saturated, partially unsaturated, or completelyunsaturated fused heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclicheteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of whichis optionally substituted; each R₄ is independently optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedheteroaryl, or optionally substituted heterocycloalkyl, halogen, —OR,—SR, —N(R′)(R″), —CN, —NO₂, —C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″),—C(O)SR, —C(O)C(O)R, —C(O)CH₂C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R,—SO₂R, —SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″),—N(R′)C(S)N(R′)(R″), —N(R′)SO₂R, —N(R′)SO₂N(R′)(R″), —N(R′)N(R′)(R″),—N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″),—OC(O)R, or —OC(O)N(R¹)(R″); each R₅ is independently —R, halogen, —OR,—SR, —N(R′)(R″), —CN, or —NO₂; n is 0-5; q is 0, 1, or 2; and p is 1-6.9-16. (canceled)
 17. The method according to claim 8, wherein R^(C) isphenyl or a 4-7 membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur, wherein R^(C) is optionally substituted with 1-5independently selected R₄.
 18. (canceled)
 19. The method according toclaim 8, wherein R₁ is halo, alkyl, aralkyl, aryl, or heteroaryl. 20.The method according to claim 19, wherein R₁ is methyl, ethyl, propyl,i-propyl, butyl, s-butyl, t-butyl, pentyl, hexyl, or heptyl.
 21. Themethod according to claim 8, wherein R₂ is H, methyl, ethyl, propyl,i-propyl, butyl, s-butyl, pentyl, hexyl, —OR, —SR, —CN, —N(R′)(R″),—C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, or —(CH₂)_(p)R_(x). 22.The method according to claim 21, wherein R₂ is H or —(CH₂)_(p)R_(x).23. The method according to claim 22, wherein R_(x) is —N(R′)(R″),—C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(S)N(R′)(R″), —S(O)R, —SO₂R,—SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)SO₂R, —OC(O)R, —OC(O)N(R′)(R″),methyl, ethyl, propyl, i-propyl, butyl, s-butyl, pentyl or hexyl. 24.The method according to claim 8, wherein R₃ is H, methyl, ethyl, propyl,i-propyl, butyl, s-butyl, pentyl, hexyl, —OR, —SR, —CN, —N(R′)(R″),—C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(O)SR, or —(CH₂)_(p)R_(x). 25.The method according to claim 24, wherein R₃ is H or —(CH₂)_(p)R_(x).26. The method according to claim 25, wherein R_(x) is —N(R′)(R″),—C(O)R, —C(S)R, —CO₂R, —C(O)N(R′)(R″), —C(S)N(R′)(R″), —S(O)R, —SO₂R,—SO₂N(R′)(R″), —N(R′)C(O)R, —N(R′)SO₂R, —OC(O)R, —OC(O)N(R′)(R″),methyl, ethyl, propyl, i-propyl, butyl, s-butyl, pentyl or hexyl. 27-30.(canceled)
 31. The method according to claim 8, wherein the compound isselected from

or a pharmaceutically acceptable salt thereof. 32-45. (canceled)
 46. Themethod according to claim 8, wherein the cancer is diffuse large B-celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma,primary central nervous system lymphoma, or T-cell lymphoma. 47.(canceled)
 48. (canceled)
 49. A method of treating a cancer selectedfrom acute myeloid leukemia/MDS, adenocarcinoma, adenoid cysticcarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma,bone cancer, breast cancer, Burkitt's lymphoma, brain cancer, carcinoma,myeloid sarcoma, cervical cancer, colorectal cancer, diffuse largeB-cell lymphoma, esophageal cancer, follicular lymphoma,gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladdercancer, gastric cancer, head and neck cancer, intestinal cancer, kidneycancer, laryngeal cancer, leukemia, leukemia, lung cancer, lymphoma,liver cancer, small cell lung cancer, non-small cell lung cancer,mesothelioma, midline carcinoma, multiple myeloma, neuroblastoma, ocularcancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor,prostate cancer, pancreatic cancer, pharyngeal cancer, renal cellcarcinoma, rectal cancer, sarcoma, skin cancer, soft tissue sarcoma,spinal tumor, small intestine cancer, stomach cancer, testicular cancer,thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma,uterine cancer, vaginal cancer, and Wilms' tumor, in a patient in needthereof, comprising administering to the patient a compound representedby the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R_(5a) isselected from hydrogen, halo, and alkoxy; R_(5b) is selected fromhydrogen, halo, and alkyl; R^(C) is selected from phenyl, heteroaryl,and saturated heterocyclyl, wherein the group represented by R^(C) isoptionally substituted with 1 to 2 substituents independently selectedfrom halo, —CN, alkyl, alkoxy, haloalkoxy, haloalkyl, and carbamyl; andR′ is selected from hydrogen, alkyl, and alkoxyalkyl.
 50. The method ofclaim 49, wherein R_(5a) is selected from hydrogen, chloro, and methoxy.51. The method of claim 49, wherein R_(5b) is selected from hydrogen,chloro, and methyl.
 52. The method of claim 49, wherein R_(5a) andR_(5b) are simultaneously hydrogen.
 53. The method of claim 49, whereinR^(C) is selected from 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl,pyridin-4-yl, 4-trifluoromethylphenyl, 5-chloropyridin-2-yl,4-carbamylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-trifluoromethoxyphenyl, 2-methyl-4-chlorophenyl, and morpholin-4-yl.54. The method of claim 49, wherein R′ is selected from hydrogen, ethyl,and 2-methoxyethyl.
 55. The method of claim 49, wherein the cancer isacute myeloid leukemia/MDS, diffuse large B-cell lymphoma, Hodgkin'slymphoma, non-Hodgkin's lymphoma, T-cell lymphoma, primary centralnervous system lymphoma, multiple myeloma or acute leukemia.
 56. Amethod of treating a cancer selected from acute myeloid leukemia/MDS,adenocarcinoma, adenoid cystic carcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,Burkitt's lymphoma, brain cancer, carcinoma, myeloid sarcoma, cervicalcancer, colorectal cancer, diffuse large B-cell lymphoma, esophagealcancer, follicular lymphoma, gastrointestinal cancer, glioblastomamultiforme, glioma, gallbladder cancer, gastric cancer, head and neckcancer, intestinal cancer, kidney cancer, laryngeal cancer, leukemia,leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer,non-small cell lung cancer, mesothelioma, midline carcinoma, multiplemyeloma, neuroblastoma, ocular cancer, optic nerve tumor, oral cancer,ovarian cancer, pituitary tumor, prostate cancer, pancreatic cancer,pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skincancer, soft tissue sarcoma, spinal tumor, small intestine cancer,stomach cancer, testicular cancer, thyroid cancer, throat cancer,urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer,and Wilms' tumor, in a patient in need thereof, comprising administeringto the patient a compound represented by the following structuralformula:

or a pharmaceutically acceptable salt thereof.
 57. The method of claim56, wherein the cancer is acute myeloid leukemia/MDS, diffuse largeB-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-celllymphoma, primary central nervous system lymphoma, multiple myeloma oracute leukemia.